# A biomarker-driven strategy to guide the use of radiotherapy in non-small cell lung cancer

> **NIH NIH R37** · NORTHWESTERN UNIVERSITY · 2020 · $361,425

## Abstract

There is an urgent need to nominate biomarkers that are likely to predict the efficacy of radiotherapy and
accelerate their clinical translation. Efforts thus far have been limited in large part because the genetic features
regulating tumor cell survival and their frequency across and within individual cancer types had not been studied
on a large-scale. Our group completed the largest profiling effort of survival after radiation in cancer cell lines,
comprising a diverse collection of 533 genetically annotated tumor cell lines from 26 cancer types. To
complement this work, we recently initiated the systematic profiling of >1000 genetic variants that could
potentially contribute to the resistance of cancer cells to radiation. We combined results from our profiling efforts
to identify features that predict the resistance of lung cancer cells to radiation. The objective in this investigation
is to advance the clinical translation of two of the most important regulators of radiation resistance in lung cancer,
Nrf2 and Braf. The Nrf2 pathway is genetically altered in ~28% of patients with non-small cell lung cancer
(NSCLC) and cells with mutations in NFE2L2 or KEAP1 are the most highly correlated with resistance to
radiation. To identify genetic dependencies of Nrf2-active tumors, we used computational and experimental
approaches to demonstrate the frequent co-occurrence between Nrf2 and phosphoinositide 3-kinase (PI3K)
alteration in NSCLCs. Using genetic and chemical means we show that antagonizing the catalytic subunit of
PI3K, p110 (encoded by PIK3CA), decreases Nrf2 activity and reverses radiation resistance driven by this
pathway. These results provide the rationale to advance a radiosensitization strategy for patients with Nrf2-active
NSCLC by targeting PI3K. Our profiling efforts also demonstrate a critical role for BRAF, which is genetically
altered in ~7% of patients with NSCLC, in the resistance of lung cancer cells to radiation. We show, for the first
time, that BRAF kinase domain mutations confer resistance to radiation in lung cancers and that they, unlike
Nrf2 pathway alterations, are almost invariably a minor component of the tumor (i.e. they are subclonal). We use
mathematical and experimental models to show that clonal architecture has significant implications for the
likelihood of response to targeted therapies and radiation. Together, these results provide a compelling rationale
to examine the role of Nrf2 and Braf alterations in predicting outcomes after radiotherapy and advance a
genomically-guided radiosensitization strategy for patients with these tumors. If these hypotheses are correct,
our results will demonstrate that radiotherapeutic sensitizers can be selected based on both the identity and type
(clonal v. subclonal) of genetic alterations identified in a patient's cancer, prompting an evolution in the use of
radiation from a generic approach to one that is guided by the genetic composition of individual tumors.

## Key facts

- **NIH application ID:** 10089004
- **Project number:** 7R37CA222294-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mohamed E. Abazeed
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,425
- **Award type:** 7
- **Project period:** 2018-06-08 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089004

## Citation

> US National Institutes of Health, RePORTER application 10089004, A biomarker-driven strategy to guide the use of radiotherapy in non-small cell lung cancer (7R37CA222294-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089004. Licensed CC0.

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