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Published on: August 11, 2017
Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer
Yu-Ra Choi1, Eun Hye Kang1, Sunshin Kim1
1Research Institute, National Cancer Center, Goyang, Republic of Korea.
Background:
In EGFR-mutant and MET-amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours.
Methods:
We investigated the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored.
Results:
Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth.
Conclusions:
Single MET inhibition produced a short-lived response in EGFR-mutant and MET-amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.
Insights
Single MET inhibition offers a temporary response in EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors. Further research into combination therapies is required for durable efficacy and reduced toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer with EGFR mutations and MET amplification often develops resistance to EGFR inhibitors.
- Combined EGFR and MET blockade is a strategy, but associated with increased toxicity.
- This study investigates the efficacy of single MET inhibition in this resistant cancer subtype.
Purpose of the Study:
- To evaluate the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer.
- To explore acquired resistance mechanisms to single MET inhibition.
- To assess clinical response and resistance patterns in patients and cell models.
Main Methods:
- Utilized EGFR-mutant, MET-amplified lung cancer cell lines (HCC827GR).
- Examined matched clinical cases and patient-derived cells.
- Investigated downstream signaling, proliferation, and gene copy number changes (ctDNA).
- Explored resistance mechanisms and re-sensitization strategies.
Main Results:
- Single MET inhibition suppressed EGFR downstream signaling and proliferation in vitro.
- Patients showed a definite but not durable response to single MET inhibitor.
- MET gene copy number decreased in plasma ctDNA during treatment.
- Reactivation of the EGFR pathway was observed in resistant cells, which were sensitive to gefitinib.
Conclusions:
- Single MET inhibition provides a transient response in EGFR-mutant, MET-amplified lung cancer.
- Resistance mechanisms involve EGFR pathway reactivation.
- Novel combination therapies are needed for sustained efficacy and improved safety profiles.
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