# High-throughput identification of novel therapeutic targets in lung cancer from genes with altered mRNA splicing

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $163,404

## Abstract

Project Summary 
 
A major challenge for the cancer genomics community is determining which somatic mutations are contributing 
to tumorigenesis and which are “passenger” (neutral) mutations. Somatic mutations that cause altered mRNA 
splicing have recently been appreciated as oncogenic driver events, such as the case with skipping of exon 14 
in the MET proto-­oncogene. Additionally, lung cancer patients with skipping of MET exon 14 respond well to 
targeted drug inhibitors. Through computational analysis of both DNA and mRNA sequencing data of 495 lung 
cancer donor samples, we have identified 635 cases of exon-­skipping associated with somatic mutation;; 
however, we lack experimental evidence to know which of these exons might also represent oncogenic driver 
events. This project will test the hypothesis that a subset of exon-­skipping events associated with 
somatic mutations are novel oncogenic alterations. To test this hypothesis, our first aim will determine if 
previously uncharacterized exon-­skipping events, associated with somatic mutations in RAS pathway genes, 
are oncogenic. RAS pathway genes are known to be recurrently mutated in lung cancer and many are 
targetable alterations;; therefore, we will focus our initial studies on exon-­skipping events which are most likely 
to be oncogenic and most likely to lead to a therapeutic target. Our second aim will develop a novel high-­
throughput CRISPR-­Cas9 screen targeting all 635 exons to test if any of these exons are oncogenic when they 
are skipped. Our final aim will use homology-­directed CRISPR-­Cas9 to knock-­in candidate splice mutations 
and validate that these mutations cause exon-­skipping, which leads to an oncogenic gene alteration. 
Completion of this study will set the framework for more broad studies of somatic mutations that affect gene 
function through alternative splicing and to investigate novel targeted therapies.

## Key facts

- **NIH application ID:** 9868290
- **Project number:** 5R21CA238600-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Angela Norie Brooks
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,404
- **Award type:** 5
- **Project period:** 2019-02-07 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868290

## Citation

> US National Institutes of Health, RePORTER application 9868290, High-throughput identification of novel therapeutic targets in lung cancer from genes with altered mRNA splicing (5R21CA238600-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868290. Licensed CC0.

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