Mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small-cell lung cancer: clinical and molecular considerations

Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of 'de novo' (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed 'acquired resistance') to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of 'acquired' versus 'de-novo' resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether 'acquired' resistance is 'de-novo' resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.     

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer

The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority (～80–90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.     

Optimal management of patients with non-small cell lung cancer and epidermal growth factor receptor mutations

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR-activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.     

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

ABSTRACT

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting.

Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC.

Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.     

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.     

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.     

EGFR基因突变与肿瘤靶向治疗

表皮生长因子受体(epidermal growth factor receptor,EGFR)属于受体酪氨酸激酶超家族,在多种恶性肿瘤中表达。配体与EGFR结合诱导形成二聚体和构象变化,活化酪氨酸激酶及信号转导途径,产生细胞增殖、侵润、转移及抗凋亡等效应。EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)类靶向药物,如吉非替尼和厄洛替尼等已应用于临床。临床研究显示仅10%~30%患者对TKIs敏感,部分位于EGFR激酶结构域的活化突变与药物敏感性相关。检测EGFR基因突变有助于预测对药物敏感性和提高疗效。随着治疗绝大多数敏感的患者获得继发耐药性,其中约半数有继发突变T790M,降低药物对靶分子的亲和力,其他许多位于EGFR下游信号途径或旁激活途径的分子也参与耐药形成。因此,未来个体化用药和准确预测敏感性,不仅仅要分析EGFR基因,而且要综合考虑下游和其他信号途径的基因,如PI3K,K-RAS,BRAF,MET和PTEN等。     

Protein kinase inhibitors to treat non-small-cell lung cancer

Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients.

Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed.

Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Role of EGFR inhibitors in the treatment of central nervous system metastases from non-small cell lung cancer

Brain metastases (BM) are a common occurrence in patients with non-small cell lung cancer (NSCLC). Standard therapy options include whole brain radiotherapy and, in selected patients, surgery or stereotactic radiosurgery. The role of systemic treatment is controversial. There is a strong clinical rationale for the use of targeted therapies, because patients often have a poor performance status, and are not candidates for cytotoxic chemotherapy or radiotherapy, yet treatment is required to improve the extra-cranial disease. The efficacy of epidermal growth factor receptor (EGFR) inhibitors in the treatment of patients with BM from NSCLC has been reported mainly in case reports or small retrospective case series, with only a few prospective trials. Current evidence suggests that the use of EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib should be considered in patients with asymptomatic CNS involvement, when clinical characteristics suggest a high likelihood of response; these characteristics are adenocarcinoma histology, never-smoker status, female gender and East Asian ethnicity. Upfront therapy with EGFR TKIs should be strongly considered in asymptomatic patients harboring activating EGFR mutations. In symptomatic BM, radiotherapy (RT) remains the standard treatment. Based on currently available data, treatment with concurrent RT and EGFR TKIs should be investigated in experimental trials only.     

Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, caused by the presence of different clinically relevant molecular subtypes. Genetic mutations are emerging as potential biomarkers of response and treatment selection in patients with NSCLC. Over the past few years, activating mutations of epidermal growth factor receptor (EGFR) have been recognized as the most important predictor of response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib and also as a favourable prognostic factor. The RAS genes, including H-RAS, K-RAS and N-RAS, encode a family of proteins regulating cell growth, differentiation and apoptosis. Mutations in the K-RAS gene, mainly in codons 12 and 13, have been found in 20-30% of NSCLC tumor samples and occur most commonly, but not exclusively, in adenocarcinoma histology and in heavy smokers. In NSCLC, the presence of K-RAS mutations has generally been considered to be associated with worse prognosis and resistance to systemic therapy in the adjuvant as well as the metastatic setting. In early stage NSCLC, the prognostic role of K-RAS mutations has been evaluated in several studies without definitive conclusion. On the other hand, in advanced NSCLC, the presence of K-RAS mutations identifies a subgroup of patients who do not respond to EGFR-TKI therapy but, at the same time, a positive survival effect from EGFR-TKIs cannot be excluded in these patients. Similarly, K-RAS mutational status does not predict benefit from the anti-EGFR monoclonal antibody cetuximab, highlighting the biological difference between lung cancer and colorectal cancer. As a result of the lack of conclusive data, K-RAS mutations do not represent a validated biomarker for the negative selection of patients who are candidates for anti-EGFR therapy. The aim of this article is to review and discuss the data on the prognostic and predictive value of K-RAS mutations in NSCLC.     

Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer

The third-generation of epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),represented by osimertinib,has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer(NSCLC)with EGFR mutation.However,resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood.In this study,we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations.We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells,evidenced by increased levels ofγH2AX and higher intensity of the comet tail after withdrawal from cisplatin.Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK,a key kinase in DNA damage response(DDR),sensitized the resistant cells to osimertinib.Combination of osimertinib with the DNA-PK inhibitor,PI-103,or NU7441,synergistically suppressed the proliferation of the resistant cells.Mechanistically,we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest.These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair,and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.     

Small molecules with EGFR-TK inhibitor activity

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.     

Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer

INTRODUCTION: The epidermal growth factor receptor (EGFR) and its family members are involved in many aspects of tumor biological processes. Aberrant activation of the EGFR tyrosine kinase by mutations or protein overexpression is observed in various types of human cancer, including lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are highly effective in lung cancer patients who harbor active mutations in the EGFR gene. However, patients who are initially sensitive to EGFR-TKIs eventually relapse within few years. AREAS COVERED: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a high frequency of EGFR mutations. This review describes the EGFR mutations that determine the sensitivity to EGFR-TKIs and the current understanding of the molecular mechanisms of acquired resistance to EGFR-TKIs in NSCLC. Furthermore, the authors describe recent strategies developed to overcome acquired resistance using second-generation EGFR-TKIs and combination therapies with several molecular-targeting drugs. EXPERT OPINION: Although recent findings have contributed to our understanding of the mechanism of acquired resistance and helped the development of novel strategies to overcome such resistance, the underlying mechanisms are complex and additional research is necessary to develop effective therapeutic strategies for individual patients with lung cancer.     

Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications

Lung cancer is a lethal disease, and most cases have already disseminated at the time of diagnosis. Driver mutations in the EGFR tyrosine kinase domain (mainly deletions in exon 19 and L858R mutation in exon 21) have been identified in lung adenocarcinomas, mostly in never smokers, at frequencies of 20-60%. The EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib attain a response rate of 70% and progression-free survival of 9-13 months, although there are subgroups of patients with long-lasting remissions. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding EGFR gene amplification. The pretreatment presence of the T790M mutation, initially identified as an acquired resistance mutation to treatment with EGFR TKIs, has also been reported and may indicate a genetically distinct disease. Finally, other genetic factors, such as mRNA expression of BRCA1 and components of the NF-κB pathway, can modulate response to EGFR TKIs in EGFR-mutated patients.     

晚期非小细胞肺癌靶向治疗的研究进展

生物标志物检测使得许多晚期非小细胞肺癌(NSCLC)患者获益。近年来,针对表皮生长因子受体(EGFR)和间变性淋巴瘤激酶(ALK)突变呈阳性的NSCLC患者,以吉非替尼、厄洛替尼、阿法替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)和以克唑替尼为代表的ALK-TKI取得了卓越的疗效。但是,大多数第一代EGFR-TKI和ALK-TKI的疗效因为不可避免的继发性耐药而被减弱。目前,第三代EGFR-TKI正是基于第二代EGFR-TKI的耐药机制研发而成。除此之外,还有许多针对其他突变位点的晚期NSCLC维持治疗的靶向抑制剂。遗憾的是,针对突变比例最大的K-RAS突变,尚无疗效确切的靶向药物。因此,基于肿瘤驱动基因突变机制的探索和靶向药物的开发是目前NSCLC的研究热点。     

Targeting the EGFR T790M mutation in non-small-cell lung cancer

Introduction: The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation.

Areas covered: This review is focused on the implications of tumor heterogeneity for targeting the T790M in patients with NSCLC.

Expert opinion: Pre-clinical and clinical data suggest that the T790M is heterogeneously expressed in tumors that become resistant to first- and second-generation EGFR TKIs. These findings have important implications for the molecular diagnostic of the T790M mutation. Indeed, the analysis of both the circulating free tumor DNA (ctDNA) isolated from plasma and the tumor tissue might provide complimentary information to identify patients carrying the T790M mutation. However, further studies are needed to better understand the influence of tumor heterogeneity on the activity of drugs targeting the T790M.     

Rational combination of targeted therapies as a strategy to overcome the mechanisms of resistance to inhibitors of EGFR signaling

The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.     

Targeting the MET pathway for potential treatment of NSCLC

Introduction: The mesenchymal-epithelial transition (MET) protein is the only known receptor for hepatocyte growth factor and has recently been identified as a novel promising target in several human cancers, including NSCLC. Activation of the MET signaling pathway can occur via different mechanisms. A number of compounds targeting MET have been evaluated in clinical trials, and recent clinical data have begun to afford some insight into the tumor types and patient populations that might benefit from treatment with MET pathway inhibitors.

Areas covered: We review recent publications and information disclosed at public conferences and summarize the epidemiology of dysregulation of MET signaling, and the associations thereof with other driver genes and therapeutic inhibitors useful to treat NSCLC.

Expert opinion: The MET pathway is emerging as a target for advanced NSCLC that is either resistant to EGFR tyrosine kinase inhibitors or that arises de novo. MET inhibitors currently being evaluated in clinical trials have yielded compelling evidence of clinical activities when used to treat various solid tumors, especially NSCLC. Remaining challenges are the identification of patient populations who might benefit from the use of MET inhibitors, and the most effective diagnostic methods for such patients.     

C-MET inhibitors for advanced non-small cell lung cancer

Introduction: The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naïve patients. The challenges ahead are in the identification of the molecular subtypes that benefit most.

Areas covered: This review summarizes the current understanding of c-MET biology in relation to studies evaluating c-MET inhibitors in the treatment of NSCLC.

Expert opinion: MET inhibitors have the potential to benefit subsets of NSCLC patients with specific genetic alterations. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to MET inhibitors, whereas overexpression, amplification and point mutations of MET seem more challenging subgroups to target. Combination with other target agents, such as EGFR inhibitors, may represent a promising therapeutic strategy in specific areas (e.g. EGFR-TKI resistance).