# Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $218,790

## Abstract

PROJECT SUMMARY/ABSTRACT
Patients diagnosed with advanced stage KRAS mutant colorectal cancer have an overall survival of roughly
one year. Despite the emergence of an increased number of molecular targeted agents, the prognosis for
patients with these cancers remains poor with 5-year survival rates of <10%. Recently, progress has been
made in the clinical advancement of therapeutics directed specifically against KRASG12C mutations, which are
present in roughly five percent of colorectal tumors. However, monotherapy trials conducted with KRASG12C
targeted agents, while encouraging, have met with disappointing lack of durable responses, dictating the need
for combination approaches. EGFR is known to reactivate MAPK kinase signaling in response to downstream
intervention, an event that is further complicated by the role of the PI3K/mTOR pathway in mediating
resistance. The central hypothesis of this proposal is that a dual small molecule inhibitor that potently and
selectively targets both EGFR and PI3 kinase represents a viable treatment strategy in combination with the
KRASG12C inhibitor clinical candidate AMG-510. To test this hypothesis, we have designed small molecules that
exhibit potent and selective dual inhibition of EGFR and PI3K family members. We propose to carry out a
mouse trial of our dual EGFR/PI3K lead molecule MTX-531 in combination with AMG-510 in xenograft models
established from patients diagnosed with KRASG12C mutant colorectal cancer. Molecular profiling will be
carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling
changes that lead to progression. Responder models will be re-evaluated in confirmatory testing in head-to-
head comparison with the combination of cetuximab and AMG-510. The overall objective of this proposal is to
demonstrate preclinical proof of concept for pursuit of this development path to optimize the therapeutic
potential of MTX-531 as a precision medicine approach for the treatment of KRASG12C mutant colorectal
cancer.

## Key facts

- **NIH application ID:** 10512415
- **Project number:** 1R21CA267412-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Judith S Leopold
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $218,790
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512415

## Citation

> US National Institutes of Health, RePORTER application 10512415, Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers (1R21CA267412-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10512415. Licensed CC0.

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