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

Abstract

Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer.

Figure 1

ERBB signaling pathways. Binding of a family of specific ligands to extracellular domain of ERBB leads to formation of homo‐ and heterodimers. In this case, HER2 is a preferred dimerization partner and heterodimers containing HER2 mediate a stronger signal than homodimers. Dimerization consequently stimulates intrinsic tyrosine kinase activity of the receptors and triggers autophosphorylation of specific tyrosine residues within the cytoplasmic domain. These phosphorylated tyrosines serve as specific binding sites for several signal transducers that initiate multiple signaling pathways including mitogen‐activated protein kinase (MAPK), phosphatidyl inositol 3 kinase (PI3K)‐AKT and signal transducer and activator of transcription protein (STAT) 3 and 5 pathways. These eventually result in cell proliferation, migration and metastasis, evasion from apoptosis, or angiogenesis, all of which are associated with cancer. P85 and p110 is a regulatory and catalytic subunit of phosphatidyl inositol 3 kinase (PI3K), respectively. STAT, SRC and mTOR are also activated by ERBB sinaling. AR, amphiregulin; BTC, betacellulin; EPR, epirefulin; ERK, extracellular signal‐regulated kinase; HB‐EGFR, heparin binding EGF; MEK, MAP an ERK kinase; mTOR, mammmalian target of rapamycin; NRG, neuregulin; TGF, transforming growth factor.

Figure 2

Incidence of epidermal growth factor receptor gene (EGFR) mutations by ethnicity, gender, smoking history and histology. Data were compiled from the published reports (n = 2880).^{( 11 )}

Figure 3

(a) Distribution and frequency of 569 epidermal growth factor receptor gene (EGFR) mutations in the published reports.^{( 11 )} (b) Response rates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) according to the type of the EGFR mutations. Data were updated from our review article^{( 11 )} by adding recent papers.^{( 24} , ³⁰ , ⁶⁴ , ⁶⁵ , ^{66 )}

Figure 4

Effect of mutations and copy numbers of the epidermal growth factor receptor gene (EGFR) on response rates in patients treated with gefitinib or erlotinib. Data were updated from our review article^{( 67 )} by adding recent papers.^{( 64} , ⁶⁵ , ⁶⁸ , ^{69 )}

Figure 5

Mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). (a) Activating mutations of the EGFR gene (star) result in constitutive activation of tyrosine kinase without ligand binding. This then turns on survival signal through pathways including the PI3K/AKT pathway. Phosphorylated tyrosine residues of ERBB3 are the main binding sites for p85, a regulatory subunit of PI3K. (b) When gefitinib (G) is administered, EGFR tyrosine kinase is specifically inhibited and survival signal is shut‐won leading to apoptosis of cancer cells. (c) When secondary threonine‐to‐methionine mutation at codon 790 of the EGFR gene (T790M) is acquired, bulkier methionine residue prevents gefitinib from binding EGFR‐TK. (d) Alternatively, when MET is activated by amplification, ERBB3 is phosphorylated by MET. Even when EGFR‐TKI is inhibited by gefitinib, activation of the PI3K/AKT pathway is maintained through ERBB3 phosphorylation. In this case, co‐administration of EGFR‐TKI and MET inhibitor can block survival signal. Modified from Arteaga et al.^{( 70 )}

Figure 6

Our current view for indication of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in Japanese patients with lung cancer. Numbers in each patient subset indicate response rate or incidence of interstitial lung disease (ILD). For example, when a patient is female with activating EGFR mutation, TKI can be used from the first line therapy (a). If the risk of ILD is estimated to be low, even when the patient does not have EGFR mutation, TKI can be used somewhere in the clinical course, considering the imperfect ability of predictive power of EGFR mutation (b). In contrast, when a male patient with a heavy smoking history and with pre‐existing ILD does not harbor EGFR mutation, there is no indication for EGFR‐TKI (c). It is most difficult when patients with high risk harbor the EGFR mutation. In this case, indication should be considered on individual basis (d).

Figure 7

Possible genotype‐based therapeutic approach for lung adenocarcinomas in Japan. Numbers indicate approximate number of patients per 100 patients in Japan.