# Interrogating the role of mutant KRAS allelic imbalance and co-mutated genes in targeted therapy response of NSCLC

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Nearly 2 million people are diagnosed with lung cancer each year and it is the leading cause in cancer
related death worldwide. Standard of care for non-small cell lung cancer (NSCLC) patients has changed little
over the past several years however targeted therapies and immune checkpoint inhibitors have recently become
a promising option. The most common oncogenic drivers in NSCLC are mutations in EGFR and KRAS which
upregulate a myriad of downstream signaling pathways that promote tumor cell growth. Until recently, efforts to
develop therapeutics that directly target EGFR or KRAS have largely been met by failure. Specifically,
development of farnesyl transferase inhibitors and downstream pathway inhibitors like MEK and RAF, have not
shown improvement in survival in the clinic and resistance mechanisms are described. The discovery of
KRASG12C mutant inhibitors like AMG 510 and MRTX849 is encouraging as they have both shown promising
signs of clinical activity and promise to transform treatment of KRAS mutant cancer. These inhibitors work by
covalently binding to the reactive Cys12 locking KRAS in its inactive GDP-bound state. However, as with
previously targeted therapies, mechanisms of resistance are beginning to be described.
Utilizing precision modeling in mice, I will test the hypothesis that KRAS allelic imbalance and genetic
determinants in NSCLC drive tumor progression and confer unique responses to targeted therapies. Since our
lab has developed LSL-Kras allelic series that allows for selective targeting of the WT Kras allele, in Aim 1, I will
use CRISPR-based genome editing technology to knockout WT Kras in vivo and measure effects in tumor
burden and G12C inhibitor response. Further, I aim to understand how WT KRAS signaling contributes to the
tumor immune microenvironment and how it affects targeted treatment response. In Aim 2, I will use a patient
data guided approach to elucidate how cooperative mutations in tumor suppressors effect tumor progression
and G12C inhibitor response. This powerful genetic approach will allow me to directly interrogate ways in which
KRASG12C targeted therapy can be affected. Identifying an effective approach to disrupt KRASG12C mutant
NSCLC will have a profound impact on the clinical management of these patients. Thus, we believe our work
will contribute significant pre-clinical data to developing safe and effective targeted therapies for NSCLC and
other cancer types.

## Key facts

- **NIH application ID:** 10474286
- **Project number:** 5F31CA261061-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Bianca Diaz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-08-09 → 2025-08-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474286

## Citation

> US National Institutes of Health, RePORTER application 10474286, Interrogating the role of mutant KRAS allelic imbalance and co-mutated genes in targeted therapy response of NSCLC (5F31CA261061-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474286. Licensed CC0.

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