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Cellular and Molecular Biology

Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer

British Journal of Cancer volume 128, pages 2186–2196 (2023)Cite this article

Subjects

Abstract

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.

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Fig. 1: A case with response to single MET inhibition.
Fig. 2: Gefitinib-resistant cells sensitive to single MET inhibition.
Fig. 3: EGFR mutation status in EGFR-mutated and MET-amplified cells sensitive to single MET inhibition.
Fig. 4: Reactivation of EGFR signalling in PHA665752-resistant HCC827GR_PR cells.
Fig. 5: Different resistance mechanisms of subclones in PHA665752-resistant HCC827GR_PR cells.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank to medical illustrator Suhyun Chae for the preparation of the excellent illustrations. This study was presented in part at the 2018 American Association for Cancer Research, April 14–18, 2018, in Chicago, Illinois.

Funding

This study was supported by a National Cancer Center grant (grant number 2210740-2).

Author information

Authors and Affiliations

  1. Research Institute, National Cancer Center, Goyang, Republic of Korea

    Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, Ji-Youn Han & Youngjoo Lee

  2. Department of Pathology, National Cancer Center, Goyang, Republic of Korea

    Seog‑Yun Park

  3. Division of Hematology and Oncology, Department of Internal Medicine, National Cancer Center, Goyang, Republic of Korea

    Ji-Youn Han & Youngjoo Lee

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Contributions

Y-RC: methodology, validation, formal analysis, investigation, data curation, writing—original draft, visualisation, writing—review & editing, project administration. EHK, SK, S‑YP and J-YH: resources and methodology. YL: conceptualisation, methodology, validation, formal analysis, investigation, data curation, writing—original draft, visualisation, writing—review & editing, project administration, supervision and funding acquisition.

Corresponding author

Correspondence to Youngjoo Lee.

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Competing interests

Youngjoo Lee; consulting fee: Roche, Merck, Yuhan, Bayer. Ji-Youn Han; research grants: Roche, ONO, Pfizer and Takeda; consulting fee: Astra Zeneca, BMS, Eli Lilly, Merck, Novartis, Pfizer, Abion, Jints Bio; honoraria for lecture: Astra Zeneca, BMS, Merck, Takeda and Novartis. The remaining authors declare no competing interests.

Ethics approval and consent to participate

This study was performed with approval from the National Cancer Center Institutional Review Board (approval number NCC2016-0208). All patients provided written informed consent.

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Choi, YR., Kang, E.H., Kim, S. et al. Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer. Br J Cancer 128, 2186–2196 (2023). https://doi.org/10.1038/s41416-023-02264-4

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