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Updated: Jun 6, 2025

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and

Srilatha Simhadri1, Jillian N Carrick2,3, Susan Murphy4

  • 1Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ.

JCO Precision Oncology
|December 3, 2024
PubMed
Abstract

Insights

Targeted therapy combined with chemotherapy can overcome resistance in BRAF-V600E-mutant colon cancer. Serial monitoring of circulating tumor DNA (ctDNA) helps track clonal dynamics and treatment response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRAF-V600E-mutant colon cancer is a challenging subtype.
  • Combined BRAF, MEK, and EGFR inhibition shows promise but faces rapid resistance.

Purpose of the Study:

  • To investigate resistance mechanisms to combined BRAF/MEK/EGFR inhibition.
  • To assess the efficacy of sequential chemotherapy and targeted therapy.
  • To model clinical findings using patient-derived organoids.

Main Methods:

  • Serial monitoring of circulating tumor DNA (cfDNA).
  • Utilized organoids from BRAF-V600E-mutant mouse models.
  • Assessed drug treatment efficacy in a pediatric patient case study.

Main Results:

  • Dynamic resistance evolution to targeted therapy observed.
  • MET amplification identified as an initial resistance mechanism.
  • Sequential chemotherapy and targeted therapy cleared resistant clones.
  • Rechallenge with BRAF/EGFR inhibition showed response, indicating non-cross-resistance.
  • Organoids validated clinical findings and treatment effectiveness.

Conclusions:

  • Sequential chemotherapy and BRAF-/EGFR-directed therapy offer rational strategies for BRAF-V600E-mutant colon cancer.
  • Serial cfDNA analysis can monitor clonal dynamics during treatment.
  • Combined EGFR and BRAF/MEK therapy is not cross-resistant with chemotherapy in mismatch repair-proficient tumors.

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