# Project 3: Mechanisms and Modulators of Sensitivity and Resistance to Kinase Inhibitors in Lung Cancer

> **NIH NIH P01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $303,085

## Abstract

PROJECT SUMMARY
Acquired resistance remains a significant obstacle to optimal therapeutic outcomes for patients with lung
cancer. The long-term goals of project 3 are to elucidate mechanisms of acquired resistance to targeted
therapies in lung cancer and to develop rational strategies to forestall/overcome resistance. During the past 5
years, we have successfully identified mechanisms of acquired resistance to first- and second-generation
EGFR tyrosine kinase inhibitors (TKIs) and developed therapeutic strategies to overcome resistance mediated
by the EGFR T790M `second-site' mutation. We participated in the characterization of the mutant-selective
third-generation EGFR TKI, osimertinib, which was recently approved by the US FDA for treatment of patients
with metastatic T790M-positive EGFR-mutant lung cancer after progression on EGFR TKI therapy.
Unfortunately, acquired resistance to osimertinib has already emerged in patients. Here, we plan to build on
our extensive experience to characterize osimertinib resistance, in both the first-line setting (i.e., in the
absence of T790M) and in the second-line setting (i.e., in the presence of T790M), to parallel ongoing clinical
trials. In addition, using knowledge gained from our studies of EGFR TKI resistance, we will continue to
advance our studies of acquired resistance to ALK TKI therapy in ALK-rearranged lung cancer. Therapeutic
targeting of ALK fusion proteins with the first-generation ALK TKI, crizotinib, has shown significant clinical
activity but is limited by the development of resistant disease. Although `next generation' ALK TKIs, including
ceritinib, alectinib, ensartinib, and lorlatinib can overcome resistance to crizotinib, resistance to these more
potent ALK TKIs has already developed in patients. We will leverage our proven proficiency in defining
resistance mechanisms combined with innovative techniques – including forward genetic screens and siRNA
screens – as well as unique resources – including novel cell lines and tumor biopsy samples taken at the time
of disease progression on TKI therapy – to enhance our understanding of therapeutic resistance mechanisms
with the overall goal of delaying or overcoming TKI resistance in lung cancer.

## Key facts

- **NIH application ID:** 9999417
- **Project number:** 5P01CA129243-13
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Christine M. Lovly
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,085
- **Award type:** 5
- **Project period:** 2007-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999417

## Citation

> US National Institutes of Health, RePORTER application 9999417, Project 3: Mechanisms and Modulators of Sensitivity and Resistance to Kinase Inhibitors in Lung Cancer (5P01CA129243-13). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999417. Licensed CC0.

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