# Computational and functional discovery of isoforms driving cancer and drug resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2024 · $697,535

## Abstract

ABSTRACT
A major challenge for the cancer genomics community is determining which somatic mutations are contributing
to tumorigenesis, which are “passenger” (neutral) mutations, and which mutations will inform personalized
treatment decisions. Unfortunately, most functional studies of cancer mutations have largely ignored the impact
of altered RNA processing even though this alteration is widespread in cancer, and is a mechanism of both
oncogenesis and therapeutic resistance. We hypothesize that we are missing critical information about cancer
gene alterations when not considering isoform-specific functions and this is likely to affect cancer treatment.
Given the breadth in the lack of understanding of isoform-specific cancer gene function, high-throughput
approaches are vitally needed to identify cancer gene isoform variants and functionally characterize their effect
on cancer development and treatment. Aim 1 of this study will generate a compendium of human pan-cancer
gene isoform variants by performing long-read transcriptome sequencing on a panel of cancer cell lines and
primary lung tumors to build a comprehensive set of allele-specific, full-length transcript isoforms. Aim 2 will
identify gene isoform variants associated with resistance or variable response to targeted therapies in
patient-derived specimens and xenograft models. Aim 3 will perform high-throughput in vitro and in vivo
functional characterization of these isoforms driving oncogenesis and drug resistance with and without somatic
mutation to identify isoform-specific variant function. All of these aims will focus on genes in the RAS-RTK
pathway since this is the most frequently mutated oncogenic pathway and contains many targetable genes.
Completion of this study will revolutionize our understanding of isoform-specific functions of cancer genes and
their contribution to oncogenesis and cancer treatment. Our approach will provide the cancer research
community with a much-needed framework and methodology for other cancer studies and will provide critical
insight into mechanisms of tumor response and resistance to cancer therapies.

## Key facts

- **NIH application ID:** 10905826
- **Project number:** 1R01CA284585-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Alice Berger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $697,535
- **Award type:** 1
- **Project period:** 2024-02-14 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905826

## Citation

> US National Institutes of Health, RePORTER application 10905826, Computational and functional discovery of isoforms driving cancer and drug resistance (1R01CA284585-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10905826. Licensed CC0.

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