Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance

Abstract

The clinical success of EGF receptor (EGFR) inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Two reports in this issue of Cancer Discovery uncover additional mechanisms by which EGFR-mutant lung cancers escape from EGFR kinase inhibitor treatment. These findings pave the way for clinical testing of new rational therapeutic strategies to prevent or overcome resistance to EGFR kinase inhibitors in the clinic.

©2012 AACR.

Figures

Figure 1. Mechanisms of acquired resistance to EGFR inhibitors and emerging pharmacologic approaches to overcome resistance

(A) The relative frequency of specific oncogenic driver mutations in lung adenocarcinomas. Red wedge indicates the frequency of somatic activating mutations in EGFR (L858R or in frame exon 19 deletion). (B) The spectrum and frequency of known drivers of acquired resistance to EGFR inhibitor therapy in lung cancer. Two new drivers of acquired resistance are described in this issue of Cancer Discovery: MAPK1 amplification was seen in ~ 5% of patients (Ercan et al.) and HER2 amplification in ~ 12% of patients (Takezawa et al). Transformation to small cell lung cancer and epithelial to mesenchymal transition (EMT) have also been described as resistance mechanisms, however the frequency and degree to which these events drive EGFR TKI acquired resistance and the molecular pathways underlying these events have not been fully defined. (C) Schematic of pathways to EGFR inhibitor acquired resistance and pharmacologic approaches in development to overcome them. EGFR T790M mutation is the dominant driver of EGFR inhibitor resistance (50–60%). Second generation EGFR TKI inhibitors BIBW2992 (afatinib), PF299804 (dacomitinib), and WZ4002 covalently bind to EGFR and have shown promise as EGFRT790M inhibitors in preclinical studies. HER2 amplification may promote acquired resistance through heterodimerization with EGFR and activation of downstream signaling events (i.e. ERK and AKT). The combination of BIBW2992 together with the EGFR monoclonal antibody cetuximab or panitumumab can inhibit both EGFR and HER2 activity in cellular and murine models of EGFR-mutant driven lung cancer. MAPK1 amplification leads to increased ERK expression and elevated phospho-ERK levels. This may promote acquired resistance by promoting EGFR internalization. Inhibition of MEK activity by GSK-1120212 decreases ERK phosphorylation and overcomes acquired resistance driven by ERK overexpression in cellular and murine models. Upregulation AXL kinase activity occurs in 20–25% of patients with acquired resistance to EGFR inhibitors and may act through downstream effectors including NF-kappaB and AKT or by promoting EMT. XL-880 is an AXL inhibitor in clinical development that can overcome AXL-mediated resistance to erlotinib in models of EGFR-mutant lung cancer. MET amplification and PIK3CA mutations have has been described in ~ 5% of patients with acquired resistance. Several MET and PI3K inhibitors are in clinical development and testing.

Figure 1. Mechanisms of acquired resistance to EGFR inhibitors and emerging pharmacologic approaches to overcome resistance

(A) The relative frequency of specific oncogenic driver mutations in lung adenocarcinomas. Red wedge indicates the frequency of somatic activating mutations in EGFR (L858R or in frame exon 19 deletion). (B) The spectrum and frequency of known drivers of acquired resistance to EGFR inhibitor therapy in lung cancer. Two new drivers of acquired resistance are described in this issue of Cancer Discovery: MAPK1 amplification was seen in ~ 5% of patients (Ercan et al.) and HER2 amplification in ~ 12% of patients (Takezawa et al). Transformation to small cell lung cancer and epithelial to mesenchymal transition (EMT) have also been described as resistance mechanisms, however the frequency and degree to which these events drive EGFR TKI acquired resistance and the molecular pathways underlying these events have not been fully defined. (C) Schematic of pathways to EGFR inhibitor acquired resistance and pharmacologic approaches in development to overcome them. EGFR T790M mutation is the dominant driver of EGFR inhibitor resistance (50–60%). Second generation EGFR TKI inhibitors BIBW2992 (afatinib), PF299804 (dacomitinib), and WZ4002 covalently bind to EGFR and have shown promise as EGFRT790M inhibitors in preclinical studies. HER2 amplification may promote acquired resistance through heterodimerization with EGFR and activation of downstream signaling events (i.e. ERK and AKT). The combination of BIBW2992 together with the EGFR monoclonal antibody cetuximab or panitumumab can inhibit both EGFR and HER2 activity in cellular and murine models of EGFR-mutant driven lung cancer. MAPK1 amplification leads to increased ERK expression and elevated phospho-ERK levels. This may promote acquired resistance by promoting EGFR internalization. Inhibition of MEK activity by GSK-1120212 decreases ERK phosphorylation and overcomes acquired resistance driven by ERK overexpression in cellular and murine models. Upregulation AXL kinase activity occurs in 20–25% of patients with acquired resistance to EGFR inhibitors and may act through downstream effectors including NF-kappaB and AKT or by promoting EMT. XL-880 is an AXL inhibitor in clinical development that can overcome AXL-mediated resistance to erlotinib in models of EGFR-mutant lung cancer. MET amplification and PIK3CA mutations have has been described in ~ 5% of patients with acquired resistance. Several MET and PI3K inhibitors are in clinical development and testing.