# Project-002

> **NIH NIH U54** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $463,293

## Abstract

Receptor Tyrosine Kinase (RTK) inhibitors have revolutionized the treatment of several cancer types, but the
eventual emergence of acquired resistance remains a major limitation of clinical benefit. Recent studies by our
group and others have shown that acquired resistance is often characterized by extensive tumor
heterogeneity, with multiple resistance mechanisms emerging simultaneously in distinct tumor subclones within
an individual patient. This heterogeneity presents a formidable therapeutic obstacle, as therapies designed to
overcome one specific resistance mechanism may be unable to suppress subclones harboring other
resistance mechanisms, leading to clonal outgrowth and treatment failure. To develop and model strategies to
overcome heterogeneous resistance to RTK inhibitors, we will perform a comprehensive assessment of
acquired resistance to MET inhibition. MET is a critical RTK that is of growing therapeutic importance, with
dramatic responses observed with MET inhibitors in the ~4% of gastroesophageal cancers (GEC) with MET
amplification and ~5% of non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping. We will
employ a systematic liquid biopsy platform for circulating tumor DNA analysis, coupled with serial tumor
biopsies, and a rapid autopsy program, to define the molecular landscape and heterogeneity of acquired
resistance to MET inhibition. Through detailed mechanistic studies, we will attempt to identify common
signaling nodes upon which multiple resistance mechanisms converge, which may represent “universal”
targets to intercept multiple heterogeneous resistance mechanisms simultaneously. We will also evaluate the
potential for sequential inhibition strategies coupled with real-time ctDNA monitoring to overcome multiple
resistance mechanisms that do not share a common signaling output. These approaches have the potential to
create a new standard for surmounting tumor heterogeneity in the setting of acquired resistance, and we
anticipate that principles defined by these studies will be broadly applicable to other RTK inhibitor paradigms.

## Key facts

- **NIH application ID:** 10247526
- **Project number:** 5U54CA224068-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ryan Bruce Corcoran
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,293
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247526

## Citation

> US National Institutes of Health, RePORTER application 10247526, Project-002 (5U54CA224068-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247526. Licensed CC0.

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