Related Experiment Video

Updated: Jun 5, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition

Xinxin Song1, Zhuan Zhou1, Ammar Elmezayen2

  • 1Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Science Advances
|December 11, 2024
PubMed

Insights

KRAS-G12C inhibitors face resistance in cancer. Combining SRC inhibitors with these drugs overcomes resistance by targeting JUN-ABCC1 pathway, enhancing treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS-G12C mutations drive non-small cell lung cancer (NSCLC) and pancreatic cancer.
  • Covalent inhibitors (G12Ci) targeting KRAS-G12C show promise but face emerging drug resistance.
  • Understanding resistance mechanisms is crucial for improving G12Ci efficacy.

Purpose of the Study:

  • To investigate mechanisms of MRTX849 resistance in KRAS-G12C-mutant cancers.
  • To identify therapeutic strategies to overcome MRTX849 resistance.
  • To evaluate the synergistic effects of SRC inhibitors with G12Ci.

Main Methods:

  • Genome-wide CRISPR screen to identify resistance mediators.
  • Functional studies on gene expression and drug resistance.
  • Unbiased drug screening and preclinical validation in mouse models and organoids.

Main Results:

  • ABCC1 was identified as a mediator of MRTX849 resistance via a CRISPR screen.
  • JUN transcription factor drives ABCC1 expression, leading to multidrug resistance.
  • Dasatinib, a SRC inhibitor, potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation.
  • SRC inhibitors show synergistic effects with MRTX849 in KRAS-G12C-mutant cancer models.

Conclusions:

  • SRC inhibitors can overcome G12Ci resistance by targeting the JUN-ABCC1 pathway.
  • Combining SRC inhibitors with G12Ci enhances therapeutic efficacy in KRAS-G12C-mutant cancers.
  • SRC inhibitors amplify the therapeutic potential of G12Ci for treating NSCLC and pancreatic cancer.

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