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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer
Pınar Özden Eser1,2,3,4, Raymond M Paranal1,2, Jieun Son1,2,3
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Abstract:
The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in EGFR-mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.
Insights
Drug resistance in EGFR-mutant lung cancer can arise from MET amplification. Some tumors become solely dependent on MET, suggesting single-agent MET inhibitors may be effective, challenging current combination therapy standards.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) targeted therapy efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by drug resistance.
- A key resistance mechanism involves human growth factor receptor (MET) proto-oncogene amplification, which reactivates downstream signaling pathways.
- Concurrent EGFR mutation and MET amplification historically imply codependency, leading to combination EGFR and MET tyrosine kinase inhibitor (TKI) treatment.
Purpose of the Study:
- To investigate the oncogene dependence in EGFR-mutant, MET-amplified NSCLC models.
- To determine if MET activation alone drives tumor survival in a subset of these cancers.
- To evaluate the efficacy of single-agent MET inhibition versus combination therapy.
Main Methods:
- Characterization of six patient-derived models of EGFR-mutant, MET-amplified lung cancer.
- Assessment of downstream signaling governed by MET in EGFR TKI-refractory cancers.
- In vitro and in vivo efficacy studies comparing combined EGFR/MET inhibition with single-agent MET inhibition.
- Analysis of EGFR:MET mRNA expression stoichiometry in patient tumors.
Main Results:
- Identified a subset of EGFR-mutant, MET-amplified lung cancers that exclusively rely on MET activation for survival.
- Demonstrated that MET, not EGFR, governed downstream signaling in these MET-driven models.
- Single-agent MET inhibition showed comparable efficacy to combined EGFR and MET inhibition in vitro and in vivo.
- A reduced EGFR:MET mRNA ratio correlated with MET dependence and sensitivity to single-agent MET TKIs in patient tumors.
Conclusions:
- A subset of EGFR-mutant, MET-amplified NSCLC exhibits exclusive MET oncogene dependence.
- These patients may benefit from single-agent MET TKI therapy instead of current combination regimens.
- Reduced EGFR:MET mRNA stoichiometry is a potential biomarker for identifying patients suitable for MET-targeted monotherapy.
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