# Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $412,108

## Abstract

Lung cancer is the largest cancer killer but is also a heterogeneous disease in which different
oncoproteins contribute to genetic subtypes, some of which carry specific treatments. Despite favorable
outcomes when therapies are matched to driving oncogenes, only small fraction of lung cancer patients are
treated in a targeted manners. Our goal is to optimize targeted therapy for the large proportion of lung cancer
patients harboring activating mutations in the Mesenchymal Epithelial Transformation (MET) gene.
Background: MET mutations are the most recent addition to the list of druggable, recurrently mutated kinases in
nonsmall cell lung cancer (NSCLC). We have recently defined the frequency of MET aberrations in NSCLC,
and identified exon 14 deletion in the juxtamembrane domain of MET as the most common somatic MET event.
The mechanism for its action and its susceptibility to existing targeted MET therapies is however poorly defined,
preventing targeted treatment of this large population of NSCLC patients.
Methods: We will focus on the many effects MET exon 14 mutations may have on the kinase, with the goal of
understanding how this mutation drives cancer. We will first characterize the juxtamembrane segment of MET
regulates the kinase. Next, we will study how exon 14 deletions affect MET inhibitors' binding and whether
mutation confers affinity for specific classes of kinase inhibitors. Finally, we will model prototypical resistance
mutations to first generation (Type I) MET inhibitors in vivo, and suggest strategies to overcome them using
targeted approaches with Type II inhibitors.
Impact: This project focuses on a common and understudied mutation in lung cancer, the most lethal cancer
type, by far. Thousands of Americans die each year with MET-mutated lung cancer, and often do so without
being considered for targeted therapy against their tumor's genotype. We will clarify the role MET mutation
plays in lung cancer and will structurally define how the most common mutations activate this oncoprotein.
This project will foster development of therapies targeting MET exon 14 mutations, and optimize approaches to
targeting the most common anticipated routes of resistance.

## Key facts

- **NIH application ID:** 10127600
- **Project number:** 5R01CA239604-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric Collisson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,108
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127600

## Citation

> US National Institutes of Health, RePORTER application 10127600, Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations (5R01CA239604-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10127600. Licensed CC0.

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