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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

A Pathak1, S Rajappa2, A Gore3,  
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

Correspondence Address:
Dr. A Pathak
Department of Oncology, Cancer Care Clinic and Hospital, Nagpur
India

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.



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;54:1-8


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 ];54:1-8
Available from: http://www.indianjcancer.com/text.asp?2017/54/5/1/221919


Full Text



 Introduction



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}

 Oncogenic Drivers



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}

 Epidermal Growth Factor Receptor Mutation



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



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



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



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



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



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



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



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



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



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



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



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}

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



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



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



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



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



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}

 Secondary Epidermal Growth Factor Receptor Mutation



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}

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



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



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



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



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



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

Nil.

Conflicts of interest

There are no conflicts of interest.

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