MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

Abstract

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Molecular pathology of lung cancer: key to personalized medicine

“…232 In vitro studies have shown that MET amplification is associated with increased concentrations of phosphorylated hepatocyte growth factor receptor. 53 Amplification of MET correlated with a poor prognosis in a study of surgically resected lung cancers, including 241 adenocarcinomas, 139 squamous cell carcinomas, and 67 other types of tumors. 231 Aberrant MET signaling may have a key role in the development of acquired resistance to therapy with an EGFR TKI.…”

“…The ligand binding-induced dimerization results in cross-autophosphorylation of key tyrosine residues in the cytoplasmic domains, which function as docking sites for downstream signal transducers. 36 This activation of EGFR initiates signaling cascades involving several downstream pathways, which induce crucial cellular responses, such as proliferation, differentiation, motility, and survival 13,[52][53][54][55][56][57][58][59][60][61][62] (Figure 1).…”

“…Despite impressive initial clinical responses, patients with EGFR-mutated adenocarcinomas almost inevitably develop drug resistance after B1 year of TKI treatment. 185,186 Studies have revealed several molecular mechanisms that may contribute to the development of tumor resistance to TKI therapy, 71,84,186,187 including acquired secondary EGFR mutation, activation of alternative signaling pathways that bypass the EGFR pathway, overexpression of HGF, 122 tyrosine protein kinase MET amplification, 53,124 epigenetic factors, 188 constitutive activation of signaling pathways downstream of EGFR, 13,189 tumor stromal and extracellular matrix alterations, 190,191 or host-related mechanisms such as rapid drug inactivation and ATP-binding cassette transporters efflux. 192 …”

“…[221][222][223] The discovery of other molecular resistance aberrations, such as MET kinase amplification or mutations of EML4-ALK fusion, which cause constitutive activation of RAS/RAF1/MAP2K1, has provided further insight and validation into factors limiting the therapeutic efficacy of EGFR inhibitors. 53,148,224 The mystery as to why all tumors harboring drug-sensitive EGFR mutations do not respond to treatment with EGFR TKI inhibitors is yet to be resolved. Clinical investigations have shown that the presence of other genetic alterations affecting signaling pathways downstream of EGFR may have a crucial role.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Much like intrinsic resistance, acquired resistance mutations can also affect “parallel” signaling pathways. For example, 20% of NSCLC specimens that had developed resistance to gefitinib or erlotinib show amplification of the MET oncogene (Engelman et al., 2007). Furthermore, recent studies have annotated PIK3CA mutations in NSCLC patients that developed resistance to these TKIs (Sequist et al., 2011; Turke et al., 2010).…”