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Updated: May 24, 2025

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Identification of Candidate Alterations Mediating KRASG12C Inhibitor Resistance in Advanced Colorectal and Pancreatic

Khalid Jazieh1, Jill Tsai2, Sheila Solomon2

  • 1Department of Oncology, Mayo Clinic, Rochester, Minnesota.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 3, 2025
PubMed
Abstract

Insights

Resistance alterations are common in KRASG12C-mutant colorectal cancer and pancreatic cancer, potentially limiting treatment effectiveness. Identifying these genetic changes is key for improving targeted therapies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • KRAS G12C inhibitors offer treatment for advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC).
  • Primary resistance mechanisms, including alterations in KRAS, EGFR, BRAF, and MAP2K1, can reduce the efficacy of these targeted therapies.

Purpose of the Study:

  • To evaluate the genetic landscape of primary resistance alterations in KRASG12C-mutant colorectal cancer and PDAC.
  • To understand genetic factors that may limit the effectiveness of KRAS inhibitors.

Main Methods:

  • Analysis of two patient cohorts (national and Mayo) with advanced colorectal cancer or PDAC.
  • Next-generation sequencing of circulating tumor DNA (ctDNA) using Guardant360.
  • Categorization of patients into groups based on KRASG12C mutation status and presence of resistance genes.

Main Results:

  • Resistance alterations were found in a significant proportion of KRASG12C-mutant colorectal cancer (46.5-53.8%) and PDAC (16.4-36.4%) cases across cohorts.
  • The presence of resistance alterations showed a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05).

Conclusions:

  • Prevalent resistance alterations in PDAC and colorectal cancer may limit the efficacy of monotherapy.
  • Identifying these alterations is crucial for optimizing patient selection for targeted therapies.
  • Understanding resistance mechanisms can guide the development of combination therapy strategies.

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