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  In this article
 »  Abstract
 » Introduction
 » Oncogenic Drivers
 »  Epidermal Growth...
 »  Kirsten Rat Sarc...
 »  Echinoderm Micro...
 »  Mesenchymal-Epit...
 » Ros1 Rearrangement
 » BRAF Mutation
 »  Human Epidermal ...
 » RET Rearrangement
 » PIK3CA Mutation
 »  Fibroblast Growt...
 » DDR2 Mutation
 » Targeted Therapies
 »  Resistance to Ep...
 »  Mechanisms for P...
 »  Impairment of Ap...
 »  Increased Phosph...
 »  Mechanisms for A...
 »  Secondary Epider...
 »  Activation of Al...
 »  Aberrance of Dow...
 »  Histological Tra...
 »  Echinoderm Micro...
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 5  |  Page : 1-8
 

Oncogenic drivers in nonsmall cell lung cancer and resistance to epidermal growth factor receptor tyrosine kinase inhibitors


1 Department of Oncology, Cancer Care Clinic and Hospital, Nagpur, India
2 Indo-American Cancer Institute and Research Centre, Hyderabad, Telangana, India
3 Department of Medical Oncology, Prince Aly Khan Hospital, Mumbai, Maharashtra, India

Date of Web Publication29-Dec-2017

Correspondence Address:
Dr. A Pathak
Department of Oncology, Cancer Care Clinic and Hospital, Nagpur
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_505_17

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 » Abstract 


Nonsmall cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Epidermal growth factor receptor (EGFR) has been extensively studied in NSCLC as an oncogenic driver. However, the efficacy of the EGFR tyrosine kinase inhibitors (TKIs) is adversely impacted by the development of resistance. The occurrence of de novo resistance to EGFR TKIs is attributed to multiple mechanisms such as point mutations of oncogenes and chromosomal rearrangements. The development of acquired resistance to EGFR TKIs is facilitated by secondary mutations, phenotypical transformation, aberrance of downstream pathways, and activation of alternate signaling pathways. The T790M mutation is the most common mutation that accounts for about half of the acquired resistance to EGFR TKIs. This review article provides an overview of the common oncogenic drivers, targeted therapies for NSCLC, and the established mechanisms implicated in the development of resistance to the EGFR TKIs.


Keywords: Acquired resistance, oncogenic drivers, nonsmall cell cancer, T790M mutation


How to cite this article:
Pathak A, Rajappa S, Gore A. Oncogenic drivers in nonsmall cell lung cancer and resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Indian J Cancer 2017;54, Suppl S1:1-8

How to cite this URL:
Pathak A, Rajappa S, Gore A. Oncogenic drivers in nonsmall cell lung cancer and resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Indian J Cancer [serial online] 2017 [cited 2018 Oct 16];54, Suppl S1:1-8. Available from: http://www.indianjcancer.com/text.asp?2017/54/5/1/221919





 » Introduction Top


Lung cancer is the leading global cause of cancer mortality.[1] About 224,390 new cases of lung cancer were diagnosed in the USA during 2016.[2] Lung cancer constitutes 6.9% of all new cancer cases and contributes to 9.3% of all cancer mortality in India.[3] Nonsmall cell lung cancer (NSCLC) accounts for 80%–85% of all lung cancers. Adenocarcinoma (ADC) is the most common subtype of NSCLC (40%), followed by squamous cell carcinoma (SCC, 25%–30%) and large cell carcinoma (LCC, 10%–15%).[4] NSCLC and SCLC account for 92% and 8% of lung cancer cases in India, respectively. ADC (43.8%) is the most common histologic subtype of NSCLC, followed by SCC (26.2%) and LCC (8.3%) in Indian settings.[5]

Lung cancer is a heterogeneous, multifactorial disease.[6] It is unique among human solid cancers because tobacco smoking is the single risk factor that initiates sequential changes that predispose to carcinogenesis in the lungs.[7] Today, the epidemiological research is focused on exploring the pathology of lung cancer at the molecular and cellular levels [7],[9] [Figure 1]. NSCLC is characterized by oncogenic drivers that contribute to abnormal activation of signaling pathways critical to cellular proliferation and survival.[8]
Figure 1: Nonsmall cell lung cancer by histology and mutations

Click here to view



 » Oncogenic Drivers Top


Oncogenic driver mutations refer to genetic mutations that are involved in the initiation and maintenance of carcinogenesis. The knowledge about cancer initiation and progression has enhanced with genomic and transcriptomic profiling.[6] ADCs of the lung have been found to demonstrate recurrent genomic alterations [Table 1].[8],[10] The most common oncologic driver mutations include the epidermal growth factor receptor (EGFR) mutations at exons 18–21, Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene mutation at codons 12 and 13, and the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion genes.[6]
Table 1: Oncogenic drivers in lung adenocarcinomas

Click here to view



 » Epidermal Growth Factor Receptor Mutation Top


EGFR is a member of the ErbB receptor family of tyrosine kinases (TKs).[6] It is a transmembrane signaling receptor that plays a central role in cellular survival, proliferation, and invasion.[8] EGFR deregulation leading to protein overexpression is evident in up to 62% of NSCLC cases. EGFR is found to be somatically mutated in about 40% of ADCs. Activating mutations of the TK domain of EGFR contribute to ligand-independent activation of the EGFR signaling.[11] The incidence of EGFR mutation differs by ethnicity, with 10% to 15% of ADCs in Caucasians being driven by activating EGFR mutations compared to 50% in Asian populations.[12] The EGFR mutation frequency in NSCLC of ADC histology among Indian males and females was estimated to be 23% and 32%, respectively.[13]

The activating mutations of the EGFR gene occur in the first four exons (18–21) of the TK domain and are grouped into three classes. Class 1 mutations constitute 44% of all EGFR TK mutations and include the in-frame deletions in exon 19. Class 2 mutations constitute 41% of all EGFR TK-activating mutations and include single-nucleotide substitutions; which mainly occurs in exon 21, resulting in the substitution of an arginine for a leucine at codon 858 (L858R).[14] Class 3 mutations constitute 5% of all EGFR TK-activating mutations and include in-frame duplications or insertions in exon 20. Class 1 and 2 mutations account for 90% of EGFR mutations and are known as “classical” activating mutations. Such mutations occur preferentially in females, never smokers, East Asians and in tumors with ADC histology.[11]

The EGFR overexpression or constitutive mutation activates signaling cascades such as the signal transducers and activators of transcription (STAT), the mitogen-activated protein kinase pathway (MAPK) and the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathways.[15],[16] The presence of EGFR activating mutations is associated with response to EGFR TK inhibitors (TKIs) in only 70% of the cases.[17],[18] The exon 20 (T790M) mutation is less sensitive to TKIs than the in-frame deletion in exon 19 and the missense mutation in exon 21 (L858R).[15] In NSCLC cases treated with TKIs, the T790M mutation has been identified as the major causative factor for acquired drug resistance.[19],[20]


 » Kirsten Rat Sarcoma 2 Viral Oncogene Homolog Mutation Top


KRAS is a member of the Ras family of GTPases that promote cell growth and division.[21] Activating KRAS mutations include single amino acid substitutions in exons 12, 13, and 61.[8] The incidence of KRAS mutations in NSCLC is estimated to be 8%–24%.[22] KRAS mutations are most frequent in NSCLC patients with ADC histology and ever or heavy smokers from Western countries.[23]

KRAS transversion mutations are likely to manifest among former or current smokers, whereas the KRAS transition mutations are more common in never smokers.[6] The mutated KRAS proteins exhibit decreased GTPase activity that results in constitutive activation of downstream effectors, including the RAF/MEK/extracellular signal-regulated kinase (ERK) and PI3K/AKT/mTOR signaling pathways.[8] The occurrence of KRAS and EGFR mutations is mutually exclusive since KRAS is a downstream effector of the EGFR, rendering the tumors nonresponsive to the EGFR TKIs.[6],[24]


 » Echinoderm Microtubule-Associated Protein-Like 4-Anaplastic Lymphoma Kinase Rearrangement Top


ALK is a receptor TK (RTK) that is frequently involved in fusion genes. The EML4-ALK rearrangement is most commonly observed in NSCLC and manifests as the fusion of the N-terminal of the EML4 gene with ALK gene within the short arm of chromosome 2.[6],[8] Such fusion results in protein oligomerization that contributes to constitutive activation of the kinase or overexpression.[11] EML4-ALK rearrangement is associated with absent or minimal smoking history, ADC histology, and younger age at NSCLC diagnosis.[6],[8] EML4-ALK rearrangements and EGFR mutations tend to be mutually exclusive.[6]


 » Mesenchymal-Epithelial Transition Amplification Top


The mesenchymal-epithelial transition (MET) gene encodes a RTK and is located on chromosome 7. The activation of MET signaling affects multiple pathways and regulates various cellular processes such as invasion, metastasis, angiogenesis, and epithelial to mesenchymal transition (EMT). The MET gene can be altered through mutations, genomic amplification, overexpression, or alternative splicing.[6] Mutations in MET gene involving exons 2 and 14 were identified in 5% of NSCLC cases.[25] The N375S is the most common nonsynonymous mutation, the frequency of which is higher among East Asians than Caucasians. MET gene amplification is mutually exclusive with EGFR and KRAS mutations.[6]


 » Ros1 Rearrangement Top


ROS1 is a RTK that is homologous to the insulin receptor. Several ROS1 rearrangements have been observed in NSCLC, which contribute to constitutive kinase activity. ROS1 rearrangement is associated with younger age at diagnosis, never or light smokers, and ADCs of high grade.[8],[11] ROS1 rearrangement was demonstrated to occur in 0.8% of surgically resected NSCLC.[26]


 » BRAF Mutation Top


BRAF is a serine/threonine kinase that lies downstream of RAS in the RAS/RAF/MEK/ERK signaling pathway. BRAF mutation is evident in 2%–4% of NSCLCs.[8] The most common BRAF mutation is the V600E mutation, which is observed in 80% of melanoma cases. However, NSCLC cases mostly exhibit the non-V600E mutations, including the G465V or G468A mutations in the G-loop of the activation domain, and D594G and L596R mutations in the kinase domain.[11]


 » Human Epidermal Growth Factor Receptor 2 Overexpression and Mutation Top


Human epidermal growth factor receptor 2 (HER2 or ErbB2) is a membrane-bound TK in the ErbB family.[27] HER2 mutations occur in only 2% of NSCLC, but HER2 is overexpressed in 20% of NSCLC cases.[28] In-frame insertions/duplication in exon 20 lead to the constitutive receptor activation.[29] HER2 amplification is commonly seen in ADCs, but HER2 mutations are absent from tumors with EGFR or KRAS mutations.[11]


 » RET Rearrangement Top


The RET gene encodes a TK receptor that influences cellular proliferation, differentiation, and migration. KIF5B-RET fusion is the predominant RET rearrangement in NSCLC. KIF5B-RET and other RET fusions contribute to the constitutive activation of oncoproteins. RET rearrangements is known to occur in 1%–2% of lung ADCs or adenosquamous carcinomas.[8] The RET rearrangements occur mutually exclusively of mutations in EGFR, KRAS, and ALK genes.[11]


 » PIK3CA Mutation Top


PI3K are a group of intracellular lipid kinases involved in regulation of cell survival, growth, and proliferation. PIK3CA mutations are observed in 2% of NSCLC cases. PIK3CA gene that encodes for the p110α catalytic subunit of PI3K undergoes point mutation.[11] PIK3CA mutations often occur along with the EGFR and KRAS mutation in lung ADCs.[27]


 » Fibroblast Growth Factor Receptor 1 Amplification Top


Fibroblast growth factor receptor 1 (FGFR1) is a membrane-bound RTK that controls cellular proliferation.[27] High level amplification of FGFR1 (chromosome 8p) is more common in lung SCCs than ADCs.[30] FGFR1 is associated with history of smoking and it is an indicator for poor prognosis in NSCLC patients.[31] A meta-analysis involving 13 studies and 1798 patients reported FGFR1 amplification in 19% of lung SCCs.[32]


 » DDR2 Mutation Top


DDR2 is a membrane-bound RTK that controls cellular proliferation and migration.[27] DDR2 mutations have been detected in 4% of lung SCCs and they are associated with sensitivity to dasatinib.[33]


 » Targeted Therapies Top


Personalized treatment strategies for NSCLC are based on the molecular-targeted therapies that improve overall survival and extend progression free survival.[24],[34] Targeted therapy is more efficacious and less toxic compared to platinum-based chemotherapy in patients with lung ADCs.[35] However, targeted therapies are not effective for lung SCCs and platinum-based chemotherapy is the standard treatment in such cases.[36],[37]

The therapeutic management of NSCLC mandates screening of tumors for molecular biomarkers. Much research has focused on the development of agents that inhibit the EGFR mutations or amplifications, KRAS mutations, PIK3CA mutations, and ALK rearrangements.[9],[24] EFGR was one of the first molecules chosen for targeted therapy since it is the most commonly deregulated genes in NSCLC.[11] The first generation, reversible EGFR TKIs gefitinib and erlotinib were designed to block EGFR tyrosine phosphorylation through competitive, reversible binding with the ATP site on the kinase domain.[38]

The first generation EGFR TKIs were first discovered to have preferential activity in NSCLC patients with certain activating EGFR mutations.[34] Erlotinib conferred a survival advantage as second- or third-line therapy in randomized studies, while gefitinib has demonstrated survival benefit in Asians and never smokers.[39],[40] The development of second and third generation irreversible TKIs has been spurred by the growing understanding of acquired resistance from secondary mutations [24],[34] [Figure 2].
Figure 2: Mechanisms of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors

Click here to view


The newer EGFR TKIs have greater affinity for EGFR kinase domain which leads to inhibition of other members of the EGFR family. The second generation, irreversible EGFR TKIs such as afatinib and dacomitinib are indicated for EGFR mutation-positive advanced NSCLC.[34] The third-generation EGFR TKIs such as osimertinib spare the wild-type EGFR but are specific for the sensitizing and T790M mutations of EGFR. Rociletinib, HM61713, PF-06747775, EGF816, and ASP8237 are the other third generation EGFR TKIs in early clinical development. Osimertinib is the only approved EGFR TKI for the metastatic EGFR T790M mutation-positive NSCLC.[41] In the AURA III study of advanced NSCLC patients with T790M mutation and disease progression during first-line EGFR-TKI therapy, osimertinib demonstrated significantly higher efficacy than the platinum-based therapy plus pemetrexed.[42]

A network meta-analysis indicated that erlotinib, gefitinib, icotinib, and afatinib have equivalent efficacy. However, erlotinib and afatinib have higher toxicity than gefitinib and icotinib.[43] Monoclonal antibodies against EGFR such as cetuximab have also reported clinical benefit in NSCLC, with increase in overall survival among patients with high-EGFR expression.[44],[45] However, cetuximab is associated with significant adverse events such as skin rash, diarrhea, and infusion-related reactions.[46]

AKT, v-akt murine thymoma viral oncogene homolog 1; AXL, AXL receptor tyrosine kinase; BIM, BCL2-like 11 (apoptosis facilitator); ERK, extracellular signal-regulated kinase; mAb, monoclonal antibody; MET, met proto-oncogene; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; RTK, receptor tyrosine kinase; STAT, signal transducers and activation of transcription; TKI, tyrosine kinase inhibitor.


 » Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Top


The first and second generation EGFR TKIs constitutes the best first-line therapy for advanced NSCLC with EGFR mutations. However, many cases with EGFR-mutant NSCLCs demonstrate de novo resistance or acquire resistance to EGFR TKIs within 9–14 months of therapy.[38] Resistance to targeted therapy is mediated through complex mechanisms that eventually render the targeted therapies ineffective.


 » Mechanisms for Primary Resistance Top


Epidermal growth factor receptor somatic mutations

Primary resistance manifests as immediate inefficacy of EGFR TKIs in NSCLC. Intrinsic resistance to EGFR TKIs may occur rarely in the presence of classical activating EGFR mutations, but more commonly manifests in nonclassical sensitizing EGFR mutations. Point mutations in exon 18, insertions or deletions in exon 19 as well as insertions or duplications, and point mutations in exons 20 and 21 are the most common mutations in the EGFR gene among NSCLC cases. Such mutations contribute to the disequilibrium of EGFR kinase between the active and inactive states.[47] The most important and frequent primary drug-resistant EGFR mutation is the exon 20 insertion.[38]

Most of exon 20 insertion mutations contribute to reduced affinity for EGFR TKIs, whereas some insertion mutations confer at least intermediate sensitivity. The T790M mutation is rarely identified in tumors before EGFR TKI therapy. The T790M point mutation increases the affinity of EGFR for ATP and thereby limits the binding efficacy of EGFR TKIs.[38] The baseline EGFR T790M mutation is associated with poor clinical outcomes in NSCLC cases treated with EGFR TKIs.[48]

Loss of activating EGFR mutant genes leads to acquired resistance to EGFR TKIs since there is a decrease in EGFR signaling and increased addiction to both HER2/HER3 and PI3K/AKT signaling.[49] Primary EGFR mutations that less frequently known to contribute to primary resistance include G719X and L861Q.[50] T790M mutation has also been associated with primary resistance to EGFR TKIs since it restores the L858R-mutant receptors affinity for ATP to wild-type levels.[51]

Another significant mutation is the variant III (vIII) in-frame deletion of exons 2–7 in the extracellular domain that prevents EGFRvIII from binding to ligands such as EGF. The mutation contributes to structural changes in the EGFR protein that impacts the intracellular domain configuration and the ATP pocket.[52] Primary resistance could also be a result of concurrent molecular or genetic alterations that limit the sensitivity of patients with sensitizing EGFR mutations to EGFR TKI treatment.[38]


 » Impairment of Apoptosis Top


BIM is a member of the proapoptotic BCL-2 family that acts as a critical mediator of EGFR TKI-induced apoptosis in EGFR-mutant NSCLC. The tumor can evade this apoptotic process due to BIM deletion polymorphisms or low-to-intermediate levels of BIM messenger ribonucleic acid.[53] Cases with mutant EGFR and low body mass index expression before treatment have shorter progression-free survival and less tumor shrinkage after EGFR TKI therapy.[54] NSCLC patients with BIM polymorphism have significantly inferior responses to EGFR TKI treatments compared to those with wild-type BIM.[55]


 » Increased Phosphatidylinositol 3-Kinase/akt Signaling Top


Increased signaling through the PI3K/AKT pathway as a result of PTEN loss is a mechanism for intrinsic resistance to EGFR TKIs. The loss of PTEN may induce resistance by relieving the tumor's dependence on EGFR signaling.[56],[57],[58] Primary resistance to EGFR TKIs is observed with mutations in the PI3KCA and P110α subunits of PI3K due to constitutive AKT activation.[59] Insulin-like growth factor 1 receptor (IGF-1R) can induce primary resistance through crosstalk with EGFR. The activation of the PI3/AKT pathway promotes resistance by IGF-1R to the EGFR TKIs.[60]


 » Mechanisms for Acquired Resistance Top


Secondary resistance typically occurs following prolonged treatment. Acquired resistance to EGFR TKIs in NSCLC cases has been defined for the benefit of clinical research in patients with resistance to EGFR TKIs [Table 2].[61]
Table 2: Criteria for acquired resistance to EGFR TKIs in lung cancer[61]

Click here to view



 » Secondary Epidermal Growth Factor Receptor Mutation Top


A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is the main mechanism for secondary resistance to EGFR TKIs.[62] Acquired resistance is mediated by secondary mutations in the kinase domain of exon 20 at the gatekeeper T790M mutation.[19],[20] This mutation is present in >50% of NSCLC patients who are initially responsive to the TKI therapy.[63] The prevalence of the T790M mutation was estimated to be 68% using a highly sensitive locked nucleic acid polymerase chain reaction/sequencing assay following the rebiopsy of lung cancer patients with acquired resistance to EGFR TKIs.[64] A study assessing T790M mutation in TKI-naive and TKI-treated NSCLC patients indicated that the T790M mutation rate was lower for TKI-naive than TKI-treated patients [65] [Table 3].
Table 3: T790M mutation incidence

Click here to view


About half of the cases with exon 19 deletion or L858R EGFR mutation also harbor the T790 mutation. The substitution of the threonine residue, located in the ATP-binding pocket of the catalytic domain, with the methionine residue results in steric conflict with the EGFR TKIs. Moreover, the T790M mutation alters the affinity of EGFR to ATP, making ATP the favored substrate compared with EGFR TKIs.[51]

Rare EGFR point mutations that lead to resistance include D761Y, T854A, and L747S.[38] However, their mechanism for resistance remains unknown. The EGFR C797S is a tertiary substitution mutation at the binding site, changing cysteine 797 into serine, that is, essential for the covalent bonding with the drugs and confers cross-resistance to all third-generation inhibitors.[38]


 » Activation of Alternative Signaling Top


Amplification of the MET oncogene accounts for 5%–20% of acquired resistance.[75] MET overactivation occurs through increased transcription and overexpression of MET protein. The most common MET mutations occurring in NSCLC are located in the semaphorin, juxtamembrane, and the TK domains. Despite the presence of EGFR blockade, the overexpressed MET receptor contributes to a persistent ErbB3-AKT signaling by maintaining ErbB phosphorylation. Overexpression of the hepatocyte growth factor, a MET receptor ligand, also contributes to acquired resistance to EGFR TKI.[38]

The amplification of the ErbB2 gene accounts for acquired resistance in 12% of lung ADCs.[76] ErbB2 mutations, located in exon 20, are frequently associated with NSCLC cases with Asian ethnicity, female gender, never smokers, and ADC histology. The ErbB2 has strong kinase activity and is usually activated by forming heterodimers with other family members. The strong inhibition by EGFR TKIs on the wild-type-ErbB2 occurs because of the dependence of ErbB2 activation on transphosphorylation of EGFR. However, the mutation in the kinase domain of ErbB2 makes it EGFR independent and induces resistance against EGFR TKIs. A hypothesis has been postulated that cancer cells acquire resistance by the T790 mutation that increases ErbB2 heterodimerization in the absence of ErbB2 amplification. Alternatively, acquired resistance may be mediated by ErbB2 amplification without the presence of secondary mutation.[38]


 » Aberrance of Downstream Pathways Top


The IGF-1R represents another pathway for the resistance to EGFR TKIs. The mechanism for resistance entails IGF-1R activation by heterodimerization with EGFR, resulting in downstream signaling through the AKT and MAPK pathways.[38] Moreover, AKT activation is associated with AKT gene mutation, PIK3CA mutations as well as amplifications, and diminished expression of PTEN.[38] Furthermore, acquired resistance may be mediated by cell signaling pathway such as BRAF mutation, or cell receptors such as the FGFR.[77],[78],[79]

Mutant EGFR receptors also drive the expression of programmed death ligand, and the inhibition of the programmed death receptor-1 improves survival.[80] The Hedgehog (Hh) pathway has also been implicated in the acquisition of resistance to first-generation TKIs. The gene amplification of the Hh receptor, SMO, concomitantly with MET activation, is a novel mechanism of acquired resistance to EGFR TKI in EGFR-mutant NSCLC. AXL upregulation is another unique mechanism of acquired resistance in EGFR-mutant NSCLC.[38]


 » Histological Transformation Top


The histological transformation from ADC to SCLC is a little known but constant observation among EGFR-mutant NSCLCs. SCLC cells may originate from minor preexistent cells under the selection pressure of EGFR TKIs, or transdifferentiate from the ADC cells, or arise from the multipotent stem cells.[79] Moreover, EMT may manifest in a process defined by loss of polarity and cell-cell contacts by the epithelial cell layers. EMT is characterized by expression of mesenchymal components, loss of epithelial cell adhesion, and alterations in cytoskeletal components.[38]


 » Echinoderm Microtubule-Associated Protein-Like 4-Anaplastic Lymphoma Kinase Secondary Mutation and Anaplastic Lymphoma Kinase Copy Number Gain Top


The L1196M mutation is a gatekeeper mutation that renders EML4-ALK fusion protein resistant to ALK inhibition. It corresponds to the amino acid residue T790 in EGFR and induces steric interference in drug binding.[81] Moreover, an increase in ALK gene copy numbers may result in resistance. A 4–5-fold amplification of EML4-ALK may occur following crizotinib treatment for NSCLC.[24]


 » Conclusion Top


The identification of molecular biomarkers has initiated an era of personalized therapy for NSCLC. A tailored therapeutic strategy based on a common genetic marker is known to improve the outcomes of patients with NSCLC. EGFR has become an established treatment target and fostered the development of EGFR TKIs. However, the occurrence of resistance to the first generation of EGFR TKIs has contributed to the development of their second and third generations. The common acquired EGFR mutations include the T790M mutation, the L858R mutation, and the exon 19 deletions. The T790M mutation accounts for 50%–60% of resistant NSCLC cases. The molecular mechanisms for acquired resistance also include MET amplification, ErbB2 amplification, histological transformation, EMT, and other mechanisms. Future research may be directed toward developing customized treatment strategies to overcome the tumor resistance in NSCLC.

Acknowledgments

The authors acknowledge AstraZeneca Pharma India Ltd and Indegene Lifesciences for Medical writing and editing support.

Financial support and sponsorship

Financial support to authors - Nil.

The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94.  Back to cited text no. 1
[PUBMED]    
2.
American Cancer Society. Cancer Facts & Figures 2016. Atlanta, Ga: American Cancer Society; 2016.  Back to cited text no. 2
    
3.
Malik PS, Raina V. Lung cancer: Prevalent trends & emerging concepts. Indian J Med Res 2015;141:5-7.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
American Cancer Society. Lung cancer (Non-small cell). 2016.  Back to cited text no. 4
    
5.
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George K, et al. Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer 2012;49:74-81.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Luo SY, Lam DC. Oncogenic driver mutations in lung cancer. Transl Respir Med 2013;1:6.  Back to cited text no. 6
[PUBMED]    
7.
Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: Looking to the future. J Clin Oncol 2005;23:3175-85.  Back to cited text no. 7
[PUBMED]    
8.
Cardarella S, Johnson BE. The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med 2013;188:770-5.  Back to cited text no. 8
[PUBMED]    
9.
Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future. Transl Lung Cancer Res 2015;4:36-54.  Back to cited text no. 9
[PUBMED]    
10.
Lovly C, Horn L, Pao W. Molecular profiling of lung cancer. My Cancer Genome 2016. Available from: https://www.mycancergenome.org/content/disease/lung-cancer/.[Last accessed on 2017 Mar 28].  Back to cited text no. 10
    
11.
Johnson JL, Pillai S, Chellappan SP. Genetic and biochemical alterations in non-small cell lung cancer. Biochem Res Int 2012;2012:940405.  Back to cited text no. 11
[PUBMED]    
12.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-11.  Back to cited text no. 12
[PUBMED]    
13.
Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015;5:2892-911.  Back to cited text no. 13
[PUBMED]    
14.
Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817-24.  Back to cited text no. 14
[PUBMED]    
15.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81.  Back to cited text no. 15
[PUBMED]    
16.
Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006;12:7242-51.  Back to cited text no. 16
[PUBMED]    
17.
Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Jänne PA, Riely GJ, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: Results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:5267-73.  Back to cited text no. 17
    
18.
Lin L, Bivona TG. Mechanisms of resistance to epidermal growth factor receptor inhibitors and novel therapeutic strategies to overcome resistance in NSCLC patients. Chemother Res Pract 2012;2012:817297.  Back to cited text no. 18
[PUBMED]    
19.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.  Back to cited text no. 19
[PUBMED]    
20.
Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-92.  Back to cited text no. 20
    
21.
Gerber DE, Gandhi L, Costa DB. Management and future directions in non-small cell lung cancer with known activating mutations. Am Soc Clin Oncol Educ Book 2014;e353-65.  Back to cited text no. 21
    
22.
Langer CJ. Roles of EGFR and KRAS mutations in the treatment of patients with non-small-cell lung cancer. P T 2011;36:263-79.  Back to cited text no. 22
[PUBMED]    
23.
Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013;24:2371-6.  Back to cited text no. 23
[PUBMED]    
24.
Wangari-Talbot J, Hopper-Borge E. Drug resistance mechanisms in non-small cell lung carcinoma. J Can Res Updates 2013;2:265-82.  Back to cited text no. 24
[PUBMED]    
25.
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-75.  Back to cited text no. 25
[PUBMED]    
26.
Jin Y, Sun PL, Kim H, Park E, Shim HS, Jheon S, et al. ROS1 gene rearrangement and copy number gain in non-small cell lung cancer. Virchows Arch 2015;466:45-52.  Back to cited text no. 26
[PUBMED]    
27.
Oxnard GR, Binder A, Jänne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 2013;31:1097-104.  Back to cited text no. 27
    
28.
Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642-6.  Back to cited text no. 28
[PUBMED]    
29.
Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525-6.  Back to cited text no. 29
[PUBMED]    
30.
Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 2011;6:e20351.  Back to cited text no. 30
[PUBMED]    
31.
Seo AN, Jin Y, Lee HJ, Sun PL, Kim H, Jheon S, et al. FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer. Virchows Arch 2014;465:547-58.  Back to cited text no. 31
[PUBMED]    
32.
Jiang T, Gao G, Fan G, Li M, Zhou C. FGFR1 amplification in lung squamous cell carcinoma: A systematic review with meta-analysis. Lung Cancer 2015;87:1-7.  Back to cited text no. 32
[PUBMED]    
33.
Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011;1:78-89.  Back to cited text no. 33
[PUBMED]    
34.
Jotte RM, Spigel DR. Advances in molecular-based personalized non-small-cell lung cancer therapy: Targeting epidermal growth factor receptor and mechanisms of resistance. Cancer Med 2015;4:1621-32.  Back to cited text no. 34
[PUBMED]    
35.
West H, Harpole D, Travis W. Histologic considerations for individualized systemic therapy approaches for the management of non-small cell lung cancer. Chest 2009;136:1112-8.  Back to cited text no. 35
[PUBMED]    
36.
Liao RG, Watanabe H, Meyerson M, Hammerman PS. Targeted therapy for squamous cell lung cancer. Lung Cancer Manag 2012;1:293-300.  Back to cited text no. 36
[PUBMED]    
37.
Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: Emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 2012;13:e418-26.  Back to cited text no. 37
[PUBMED]    
38.
Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open 2016;1:e000060.  Back to cited text no. 38
[PUBMED]    
39.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.  Back to cited text no. 39
[PUBMED]    
40.
Chang A, Parikh P, Thongprasert S, Tan EH, Perng RP, Ganzon D, et al. Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: Subset analysis from the ISEL study. J Thorac Oncol 2006;1:847-55.  Back to cited text no. 40
[PUBMED]    
41.
Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016;9:34.  Back to cited text no. 41
    
42.
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-40.  Back to cited text no. 42
[PUBMED]    
43.
Liang W, Wu X, Fang W, Zhao Y, Yang Y, Hu Z, et al. Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One 2014;9:e85245.  Back to cited text no. 43
[PUBMED]    
44.
Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42.  Back to cited text no. 44
[PUBMED]    
45.
Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008;19:362-9.  Back to cited text no. 45
[PUBMED]    
46.
Sgambato A, Casaluce F, Maione P, Rossi A, Ciardiello F, Gridelli C, et al. Cetuximab in advanced non-small cell lung cancer (NSCLC): The showdown? J Thorac Dis 2014;6:578-80.  Back to cited text no. 46
    
47.
Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 2010;1804:559-66.  Back to cited text no. 47
[PUBMED]    
48.
Costa C, Molina MA, Drozdowskyj A, Giménez-Capitán A, Bertran-Alamillo J, Karachaliou N, et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 2014;20:2001-10.  Back to cited text no. 48
    
49.
Tabara K, Kanda R, Sonoda K, Kubo T, Murakami Y, Kawahara A, et al. Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. PLoS One 2012;7:e41017.  Back to cited text no. 49
[PUBMED]    
50.
Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189-94.  Back to cited text no. 50
[PUBMED]    
51.
Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008;105:2070-5.  Back to cited text no. 51
[PUBMED]    
52.
Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A 2006;103:7817-22.  Back to cited text no. 52
[PUBMED]    
53.
Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 2011;1:352-65.  Back to cited text no. 53
[PUBMED]    
54.
Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 2015;4:67-81.  Back to cited text no. 54
[PUBMED]    
55.
Nakagawa T, Takeuchi S, Yamada T, Ebi H, Sano T, Nanjo S, et al. EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. Cancer Res 2013;73:2428-34.  Back to cited text no. 55
[PUBMED]    
56.
Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009;69:3256-61.  Back to cited text no. 56
[PUBMED]    
57.
She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N, et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005;8:287-97.  Back to cited text no. 57
    
58.
Vivanco I, Rohle D, Versele M, Iwanami A, Kuga D, Oldrini B, et al. The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc Natl Acad Sci U S A 2010;107:6459-64.  Back to cited text no. 58
[PUBMED]    
59.
Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M, Okumura N, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008;68:6913-21.  Back to cited text no. 59
[PUBMED]    
60.
Cortot AB, Repellin CE, Shimamura T, Capelletti M, Zejnullahu K, Ercan D, et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res 2013;73:834-43.  Back to cited text no. 60
[PUBMED]    
61.
Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357-60.  Back to cited text no. 61
    
62.
Suda K, Onozato R, Yatabe Y, Mitsudomi T. EGFR T790M mutation: A double role in lung cancer cell survival? J Thorac Oncol 2009;4:1-4.  Back to cited text no. 62
[PUBMED]    
63.
Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007;25:587-95.  Back to cited text no. 63
[PUBMED]    
64.
Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 2011;17:1169-80.  Back to cited text no. 64
[PUBMED]    
65.
Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 2012;30:433-40.  Back to cited text no. 65
[PUBMED]    
66.
Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006;66:7854-8.  Back to cited text no. 66
[PUBMED]    
67.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.  Back to cited text no. 67
[PUBMED]    
68.
Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494-501.  Back to cited text no. 68
[PUBMED]    
69.
Rosell R, Molina MA, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res 2011;17:1160-8.  Back to cited text no. 69
[PUBMED]    
70.
Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12:5764-9.  Back to cited text no. 70
[PUBMED]    
71.
Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer 2014;85:19-24.  Back to cited text no. 71
[PUBMED]    
72.
Li W, Ren S, Li J, Li A, Fan L, Li X, et al. T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer 2014;84:295-300.  Back to cited text no. 72
[PUBMED]    
73.
Sun JM, Ahn MJ, Choi YL, Ahn JS, Park K. Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer 2013;82:294-8.  Back to cited text no. 73
[PUBMED]    
74.
Ye X, Zhu ZZ, Zhong L, Lu Y, Sun Y, Yin X, et al. High T790M detection rate in TKI-naive NSCLC with EGFR sensitive mutation: Truth or artifact? J Thorac Oncol 2013;8:1118-20.  Back to cited text no. 74
[PUBMED]    
75.
Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007;67:11924-32.  Back to cited text no. 75
[PUBMED]    
76.
Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: A potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2012;2:922-33.  Back to cited text no. 76
[PUBMED]    
77.
Ware KE, Marshall ME, Heasley LR, Marek L, Hinz TK, Hercule P, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One 2010;5:e14117.  Back to cited text no. 77
[PUBMED]    
78.
Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A 2012;109:E2127-33.  Back to cited text no. 78
[PUBMED]    
79.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.  Back to cited text no. 79
[PUBMED]    
80.
Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 2013;3:1355-63.  Back to cited text no. 80
[PUBMED]    
81.
Lu L, Ghose AK, Quail MR, Albom MS, Durkin JT, Holskin BP, et al. ALK mutants in the kinase domain exhibit altered kinase activity and differential sensitivity to small molecule ALK inhibitors. Biochemistry 2009;48:3600-9.  Back to cited text no. 81
[PUBMED]    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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