# Cellular mechanisms and therapeutic possibilities of inhibiting oncogenic KRAS

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $129,145

## Abstract

PROJECT SUMMARY/ABSTRACT
 KRAS is among the strongest and most frequently mutated oncogenes in cancer. Tumors with mutant
KRAS often become addicted to its presence and in inducible genetic mouse models the sudden removal of
mutant KRAS can trigger cancer regressions. However, pharmacological agents capable of inhibiting the most
prevalent KRAS mutants have remained elusive and these cancers remain among the most refractory to therapy.
The National Cancer Institute’s RAS Initiative, in close collaboration with Dr. Frank McCormick’s lab at UCSF,
recently created an exciting and unpublished new class of inhibitors that covalently bind KRAS and prevent its
translocation to the plasma membrane. Intriguingly, these compounds cause KRAS to be degraded, although
the detailed mechanism remains unclear. Experimental compounds targeting synthesis of mutant KRAS also
show great promise. We hypothesize that pharmacological inhibition of KRAS will be therapeutic in cancers
driven by KRAS mutations and that these KRAS mutant cells have a set of conditional dependencies that can
be exploited for therapeutic benefit. The three specific aims of this proposal are to 1) explore the cellular
consequences of mutant KRAS loss 2) understand the mechanistic relationship between KRAS
inhibitors and their effects on KRAS localization, production, and degradation 3) identify genetic and
pharmacological interactions that cooperate with KRAS loss. The results of this project are expected to help
elucidate the biology of one of the most critical oncogenes in cancer and pinpoint combination therapies and
susceptible genotypes with potential clinical utility. This research is expected to have a broad impact on therapy
for a variety of cancer types, with a particular emphasis on personalized genotype-specific targeted medicine.
 My research focuses on elucidating the biological mechanisms driving cancers to advance frontline
therapies and improve patient outcomes. I have proposed a comprehensive training and career development
program for the mentored (K99) phase and my transition to independent principal investigator (R00). Research
on the genetic model of mutant KRAS ablation in Aim 1A, the mechanism of KRAS degradation probed in Aim
2, and the CRISPRi and CRISPRa screens to look for cooperators with KRAS inhibition in Aim 3 are predicted
to be completed during the K99 phase. The pharmacological effects on mutant KRAS biology in Aim 1B and
biological validation and mechanistic illumination of screen hits from Aim 3 are scheduled for the R00 period.
Components of my training program include 1) guidance from my esteemed mentor Dr. McCormick for all Aims,
2) regular meetings with an expert advisory panel, 3) career development courses at UCSF, 4) online learning
resources such as the Ras Lab researcher forum, 5) hands-on training using state-of-the-art equipment and
forefront technologies, and 6) conceptual learning from Dr. McCormick and my advisory team on planning and
conducti...

## Key facts

- **NIH application ID:** 10216890
- **Project number:** 3K99CA226363-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew L Wolfe
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $129,145
- **Award type:** 3
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216890

## Citation

> US National Institutes of Health, RePORTER application 10216890, Cellular mechanisms and therapeutic possibilities of inhibiting oncogenic KRAS (3K99CA226363-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10216890. Licensed CC0.

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