Related Experiment Video

Updated: Sep 11, 2025

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

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Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in CRC

Salvador Alonso1,2, Kevan Chu1,3, Marie J Parsons1

  • 1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY.

Biorxiv : the Preprint Server for Biology
|August 13, 2025
PubMed

Insights

KRAS inhibitors show promise for colorectal cancer (CRC), but resistance is a challenge. Targeting TBK1 may overcome early inflammatory responses and enhance treatment efficacy in KRAS-mutated CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations drive 45-50% of colorectal cancer (CRC) cases.
  • KRAS-targeted therapies face upfront and acquired resistance, limiting clinical efficacy.
  • Understanding resistance mechanisms is crucial for improving CRC treatment outcomes.

Purpose of the Study:

  • To investigate the acute response and resistance mechanisms to combined KRASG12C and EGFR inhibition in colorectal cancer.
  • To identify molecular targets that can overcome drug resistance.

Main Methods:

  • Targeted exome sequencing and single-cell spatial transcriptomics on patient biopsies (pre-treatment, on-treatment, progression).
  • Analysis of genetic events and transcriptional adaptive states.
  • Utilized human and murine organoid models to study drug-induced programs.

Main Results:

  • Acquired genetic events were often subclonal and coexisted with transcriptional adaptive states at progression.
  • Mesenchymal, YAP, and fetal-like signatures predominated in resistant tumors.
  • Early treatment induced tumor cell-intrinsic inflammatory programs, preceding drug resistance-associated fetal-like programs.

Conclusions:

  • Significant intratumoral heterogeneity and diverse adaptive states contribute to resistance.
  • Drug-induced inflammatory programs are cancer-cell autonomous and precede resistance.
  • TBK1 inhibition is a potential strategy to abrogate early inflammatory responses and enhance KRAS inhibition efficacy in CRC.

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