# Project 3

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2022 · $400,742

## Abstract

PROJECT SUMMARY
Genotype directed therapy is the standard of care for the significant proportion of advanced non-
small cell lung cancer patients whose tumors harbor a targetable genetic mutation within EGFR,
ALK, ROS1, BRAF, RET, MET, NTRK or HER2. Although this therapeutic approach is effective,
acquired drug resistance inevitably occurs. The current management strategy for acquired
resistance is to evaluate the mechanism of resistance with a biopsy to help guide subsequent
treatment. However, mechanisms of resistance can be heterogenous and not all patients’ tumors
harbor an actionable resistance mechanism. Moreover, even when a targetable mechanism of
resistance is identified and a subsequent therapy available, acquired resistance will develop
again. An alternative strategy is to intervene therapeutically prior to the clinical development of
acquired drug resistance by specifically targeting the residual drug tolerant persister (DTP) cells,
a small population of cells that remain after effective genotype directed therapies and ultimately
give rise to acquired resistance. There have been no clinical strategies developed against DTPs,
in part due to the lack of the biological and mechanistic understanding of this state.
In this project we will lay the foundation for clinical therapeutic strategies aimed at DTP cells by
uncovering factors that lead to formation of the DTP state and identifying targets that can kill DTP
cells. We will build on prior research from our group centered around the DTP state in EGFR-
mutant lung cancer showing: 1) YAP/TEAD activation results in transcriptional repression of the
pro-apoptotic protein BMF and thus limits EGFR inhibitor mediated apoptosis; 2) the DTP state
displays some features of cellular senescence and anti-apoptosis agents may be an effective
strategy; and 3) cancer-associated fibroblasts in the tumor microenvironment can facilitate DTP
emergence and modulate the senescence phenotype of established DTPs. Building upon this
foundation, the experiments detailed in this project utilize a combination of innovative techniques
and a unique and large collection of patient-derived cancer and fibroblast models from
genomically-driven cancers to understand the vulnerabilities of the DTP state and design optimal
clinical approaches to combat these harbingers of drug resistance in patients.

## Key facts

- **NIH application ID:** 10496036
- **Project number:** 1P50CA265826-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pasi A Janne
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,742
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496036

## Citation

> US National Institutes of Health, RePORTER application 10496036, Project 3 (1P50CA265826-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10496036. Licensed CC0.

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