# Non-genomic resistance mechanisms in EGFR-mutant lung cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $408,487

## Abstract

Project Summary
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is the current standard of care for first-line
therapy for EGFR mutant lung cancer patients. While osimertinib is effective in inducing tumor regressions,
improving quality of life and prolonging survival in most patients, it is not curative. Early studies of acquired
resistance suggest that even after standard histologic and genomic assessments for resistance mechanisms, a
substantial portion of osimertinib resistance remains uncharacterized. This incomplete understanding of
osimertinib resistance poses a significant barrier to developing new and effective therapies for clinical use. We
hypothesize that, in contrast to earlier generation EGFR inhibitors, non-genomic mechanisms are driving the
majority of acquired resistance to first-line osimertinib. To date, assessments of EGFR TKI acquired resistance
mechanisms have focused on genomic resistance mutations, amplifications, and fusions, in part because these
can be readily detected in tumor tissue or in blood-based ctDNA liquid biopsies. In this project we seek to
discover the spectrum of non-genomic osimertinib resistance. Our main objective is to identify both tumor intrinsic
mechanisms of osimertinib resistance as well as tumor extrinsic microenvironmental resistance mechanisms. In
Aim 1, we will use RARE-Seq, a novel blood-based assay to quantify tumor gene expressions patterns of
resistance in EGFR mutant NSCLC patients relapsing on osimertinib. In Aim 2, we will investigate tumor cell
extrinsic mechanisms of osimertinib resistance by leveraging our robust translational infrastructure to develop
cancer-associated fibroblast models from osimertinib resistance biopsies. We will use these models to dissect
functional interactions between CAFs, tumor cells and immune cells, and we will integrate these results with
spatial molecular analysis of clinical biopsies. Collectively, the studies described in this proposal will generate a
comprehensive picture of osimertinib resistance and set the stage for future development of therapies that
overcome resistance to osimertinib.

## Key facts

- **NIH application ID:** 10442329
- **Project number:** 2R01CA137008-11A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Aaron N Hata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $408,487
- **Award type:** 2
- **Project period:** 2009-03-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442329

## Citation

> US National Institutes of Health, RePORTER application 10442329, Non-genomic resistance mechanisms in EGFR-mutant lung cancer (2R01CA137008-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10442329. Licensed CC0.

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