# Cellular mechanisms and therapeutic possibilities of inhibiting oncogenic KRAS

> **NIH NIH R00** · HUNTER COLLEGE · 2021 · $249,000

## 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UCSF, recently created an exciting and unpublished new class of inhibitors that covalently bind KRAS and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. 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 degradation and localization 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 conducting experiments. This extensive research and professional development program will
guide me duri...

## Key facts

- **NIH application ID:** 10455115
- **Project number:** 4R00CA226363-03
- **Recipient organization:** HUNTER COLLEGE
- **Principal Investigator:** Andrew L Wolfe
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2018-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455115

## Citation

> US National Institutes of Health, RePORTER application 10455115, Cellular mechanisms and therapeutic possibilities of inhibiting oncogenic KRAS (4R00CA226363-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10455115. Licensed CC0.

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