Related Experiment Video

Updated: Aug 11, 2025

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
09:29

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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A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E

Ana Ruiz-Saenz1,2, Chloe E Atreya1, Changjun Wang1,3

  • 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Nature Cancer
|February 9, 2023
PubMed

Insights

SRC kinases drive resistance to targeted therapies in BRAF-mutant colorectal cancer (CRC). Co-targeting SRC with BRAF and EGFR inhibitors, or using COX2 inhibitors, overcomes this resistance, improving treatment efficacy in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • BRAF V600E mutation is linked to poor prognosis in metastatic colorectal cancer (CRC).
  • Current targeted therapies for BRAF V600E CRC, including BRAF-MEK-EGFR co-targeting, face resistance.
  • Understanding parallel resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

  • To identify resistance mechanisms in BRAF V600E CRC treated with BRAF-MEK-EGFR inhibitors.
  • To evaluate the efficacy of co-targeting SRC kinases or using COX2 inhibitors to overcome resistance.

Main Methods:

  • High-throughput kinase activity mapping platform.
  • In vitro and in vivo preclinical models of BRAF V600E CRC.
  • Patient-derived tumor xenograft models.

Main Results:

  • SRC kinases are activated upon BRAF ± EGFR inhibition in BRAF V600E CRC.
  • Co-targeting SRC with BRAF ± EGFR enhances treatment efficacy.
  • SRC-mediated resistance occurs independently of ERK signaling via CTNNB1 transcriptional reprogramming.
  • An autocrine prostaglandin E2 loop involving COX2 mediates SRC activation.
  • Co-targeting COX2 with BRAF + EGFR inhibitors leads to durable tumor growth suppression.

Conclusions:

  • SRC kinase activation is a key resistance mechanism to BRAF ± EGFR targeted therapy in BRAF V600E CRC.
  • Combined inhibition of SRC or COX2 with BRAF ± EGFR represents a viable strategy to overcome therapeutic resistance.
  • COX2 inhibition offers a drug-repurposing opportunity for treating BRAF V600E CRC.

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