# Resistance and Sensitivity to MET Inhibitors in Lung Cancer

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $390,403

## Abstract

PROJECT SUMMARY
Genotype directed therapy is the standard of care for patients with advanced non-small cell lung cancer
(NSCLC). For patients with advanced epidermal growth factor receptor (EGFR) mutant, anaplastic lymphoma
kinase (ALK) or ROS1 rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are the standard of care initial
systemic therapies. However, not all NSCLC patients harbor a targetable genomic alteration and even among
those that can be initially treated with a TKI, acquired resistance inevitably develops. MET is a transmembrane
receptor tyrosine kinase implicated in various aspects of malignancy including tumor growth, survival, invasion,
migration, angiogenesis and metastasis. Aberrant alterations in the MET gene, leading to ligand (hepatocyte
growth factor; HGF) independent activation of MET signaling, including mutations, copy number gains and
rearrangements have been observed in many malignancies including in lung cancers. Several therapeutic
strategies to inhibit MET signaling such as TKIs, antibodies targeting the MET receptor or HGF, have been
developed and are undergoing clinical evaluation. As several clinical approaches to target MET in lung cancer
have been unsuccessful as a result of selecting patients based on an ambivalent biomarker (MET
immunohistochemistry (IHC); METMab) or using agents that were subsequently discovered not to be true MET
inhibitors (Tivantinib (ARQ 197)), genomic alterations in MET have proven to be more reliable predictors of the
clinical efficacy of MET inhibitors. In EGFR mutant NSCLC, MET amplification is a mechanism of acquired
resistance to EGFR TKIs and the combination of EGFR and MET directed therapies is an effective therapeutic
approach for such patients. De novo MET amplification and MET exon 14 skipping mutations have emerged as
genomic alterations that predict for the clinical efficacy of single agent MET inhibitors. Intriguingly, some EGFR
mutant MET amplified cancers also respond to single agent MET inhibition. The mechanistic basis for this is
unknown. Of these different MET altered populations, MET exon 14 mutations are the most common (~ 3% of
all lung adenocarcinomas) and multiple clinical trials are currently underway evaluating single agent MET TKIs
in MET exon 14 mutant NSCLC. However, despite the clinical efficacy of MET TKIs in such cancers, acquired
resistance will inevitably develop. Accordingly, we plan to investigate the mechanisms of acquired resistance to
MET targeted therapies and determine whether drug resistant cancers retain their MET dependency. The
mechanistic understanding of acquired drug resistance may help determine whether an alternative MET
inhibitor (in the presence of a secondary MET mutation) or a combination (targeting a parallel or downstream
signaling pathway) is likely to be therapeutically effective. We are accomplishing this through the following
specific aims: Aim 1: To determine impact of MET mutations on efficacy of MET inhibitors; Aim 2: To
unde...

## Key facts

- **NIH application ID:** 9847953
- **Project number:** 5R01CA222823-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pasi A Janne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,403
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847953

## Citation

> US National Institutes of Health, RePORTER application 9847953, Resistance and Sensitivity to MET Inhibitors in Lung Cancer (5R01CA222823-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847953. Licensed CC0.

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