# Targeting Acquired Resistance in KRAS Driven Cancers

> **NIH NIH R37** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $420,385

## Abstract

Development of treatment resistance is a major impediment to effective cancer therapy. KRASG12C inhibitors
(KRASi) have been recently approved by FDA and represents a promising new targeted therapy for cancer types
with KRAS mutation, one of the most frequent genetic mutations observed in human cancers. However, as is
the case with standard therapy, majority of tumors that initially respond to KRASi quickly develop resistant
disease. Unfortunately, the underlying mechanisms of KRASi resistance are poorly understood. To tackle this
challenging problem, this application will capitalize on the PI's track record and expertise in the area of KRAS
signaling and biology and propose a comprehensive research program focusing on understanding the
mechanisms of acquired resistance to KRAS targeted therapy. This application will identify new actionable
therapeutic targets and approaches to overcome resistance, thus greatly improving the clinical outcome of
patients with KRAS mutated cancers. To achieve this, the Yao laboratory has developed in vitro and in vivo
model systems that will be employed to investigate hypotheses regarding mechanisms driving the development
of KRASi resistance. The in vitro model system consists of KRAS dependent and independent cell cultures
derived from genetically engineered mouse models of pancreatic cancer as well as human cancer cell lines of
pancreatic and colon origin. The in vivo model system consists of patient-derived colon cancer models that
developed resistance to KRASi, as well as genetically engineered mouse models of pancreatic cancer driven by
KRASG12C. The major knowledge gaps to be addressed are that: i) what molecular events are activated to enable
bypass of KRAS dependency in tumors treated with KRASi; ii) how these molecular events function to drive
tumor survival and maintenance in response to KRASi; and iii) whether pharmaceutically targeting the resistant
mechanism can achieve durable therapeutic responses in combination with KRASi. These studies will unveil a
previously unknown mechanism by which tumor cells become resistant to KRAS targeted therapy and may
define an innovative therapeutic option for KRASi-resistant patients. The proposed work comprises an essential
step toward our long-term goal of developing effective therapy for patients with KRAS mutated cancer, in align
with the mission of the National Cancer Institute (NCI) RAS initiative (“Kill RAS”).

## Key facts

- **NIH application ID:** 10895586
- **Project number:** 5R37CA272744-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Wantong Yao
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,385
- **Award type:** 5
- **Project period:** 2022-08-12 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895586

## Citation

> US National Institutes of Health, RePORTER application 10895586, Targeting Acquired Resistance in KRAS Driven Cancers (5R37CA272744-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10895586. Licensed CC0.

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