# Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $348,207

## Abstract

The use of genomically targeted therapies has improved treatment response and clinical outcomes for 
molecularly defined subsets of patients with non-small cell lung cancers. While responses to these therapies 
can often be dramatic, they are rarely durable, and there is a significant need to improve the duration of 
response and delay or prevent treatment resistance. Studies from our group and others have characterized the 
properties of cancer cells which escape initial treatment with a targeted agent. Analyses of these data have 
revealed transcriptional and epigenetic adaptation as a requirement for the survival of cells that persist in the 
face of targeted therapy. 
Working with Core A (Chemistry) and Core B (Structure), we have obtained Preliminary Data suggesting that 
inhibitors of higher-order cyclin dependent kinases (CDKs), enzymes which perform key roles in transcriptional 
initiation and elongation, display potent synergy with targeted kinase inhibitors in a diverse array of NSCLC 
models both in vitro and in vivo. Specifically, we have identified THZ1, a covalent CDK7/12 inhibitor designed 
by Core A leader Dr. Gray, as a tool compound which synergizes with inhibitors of EGFR (Project 1), MEK 
(Project 2) as well as ALK, HER2, BRAF, FGFR and PI3K in genetically selected NSCLC models. In this 
project, we will advance our efforts in targeting transcriptional adaptation to targeted therapies by using genetic 
tools to define the key CDK/cyclin genes responsible for therapeutic synergy and using this information to 
design more selective CDK inhibitors and selective degraders with improved specificity and in vivo 
pharmacology as compared to THZ1. Further, we will use transcriptional and epigenetic analysis to define the 
mechanisms governing therapeutic synergy among targeted therapies and CDK inhibitors. This project will be 
amenable to clinical translation given the broad applicability of this approach and ongoing efforts to develop 
transcriptional CDK inhibitors for clinical use.

## Key facts

- **NIH application ID:** 10003961
- **Project number:** 5P01CA154303-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Matthew L. Meyerson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,207
- **Award type:** 5
- **Project period:** 2012-05-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003961

## Citation

> US National Institutes of Health, RePORTER application 10003961, Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer. (5P01CA154303-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10003961. Licensed CC0.

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