# Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2021 · $1,047,525

## Abstract

Project Summary
The use of genotype directed precision therapies, including epidermal growth factor receptor (EGFR) and
anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in EGFR mutant or ALK rearranged non-
small cell lung cancer (NSCLC), respectively, is associated with improvements in both response rate (RR) and
progression free survival (PFS) compared to chemotherapy. However, the PFS improvements are typically
only counted in months rather than years. Despite the development of next generation TKIs that can overcome
specific resistance mechanisms, it is very unlikely that any patient will be cured from their advanced lung
cancer using sequential single agent treatment. It is more than likely that significant improvements in patient
outcomes using precision therapies will only occur through the use of combination therapies. In the current
proposal we integrate pre-clinical in vitro and in vivo studies, with clinical trials and serial non-invasive analyses
of patient's tumors using cell free DNA to develop combination therapies. We focus primarily on EGFR mutant
lung cancer as this is the largest subset of NSCLC patients treated with precision therapies and as there is a
desperate need to developing more effective therapies for EGFR mutant patients. The approaches to
developing combination therapies include a.) dual targeting of EGFR, b.) vertical pathway inhibition (combining
EGFR inhibition with downstream signaling inhibition) and c.) parallel pathway inhibition (combining EGFR
inhibition with other signaling pathways). Our strategy will focus on improving therapies for EGFR inhibitor
naïve cancers, as such cancers are genetically the most homogeneous, and where improving treatment
approaches will likely translates into the greatest clinical benefit by delaying and/or preventing the emergence
of acquired drug resistance. Our preclinical studies provide the rationale for the combination clinical studies
and their success (or lack thereof) and toxicity in the clinic will inform about additional preclinical approaches to
further refine treatments. Through this iterative process, our goal is to make significant improvements in the
outcome of EGFR mutant and other lung cancer patients treated with genotyped directed therapies.

## Key facts

- **NIH application ID:** 10246360
- **Project number:** 5R35CA220497-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pasi A Janne
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,047,525
- **Award type:** 5
- **Project period:** 2018-09-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246360

## Citation

> US National Institutes of Health, RePORTER application 10246360, Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance (5R35CA220497-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246360. Licensed CC0.

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