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Updated: Apr 22, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

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Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution

Sandra Misale1, Federica Di Nicolantonio1, Andrea Sartore-Bianchi2

  • 1Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.

Cancer Discovery
|October 9, 2014
PubMed
Abstract

Insights

Resistance to epidermal growth factor receptor (EGFR) targeted therapies in metastatic colorectal cancer arises from similar gene mutations causing primary and acquired resistance. These diverse genetic mechanisms converge on key pathways for new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Epidermal growth factor receptor (EGFR)-targeted antibodies, such as cetuximab and panitumumab, are standard treatments for metastatic colorectal cancer (mCRC).
  • Primary resistance to anti-EGFR therapy is often driven by specific genetic alterations, including mutations in KRAS, NRAS, BRAF, and amplification of ERBB2 and MET.

Purpose of the Study:

  • To investigate the genetic landscape of both primary (de novo) and acquired (secondary) resistance to anti-EGFR antibodies in metastatic colorectal cancer.
  • To identify commonalities and divergences in the molecular mechanisms underlying resistance to EGFR-targeted therapies.

Main Methods:

  • Review of existing literature on genetic alterations associated with resistance to EGFR-targeted therapies in mCRC.
  • Analysis of studies reporting primary resistance mechanisms and acquired resistance mechanisms in patients treated with anti-EGFR antibodies.

Main Results:

  • A significant overlap exists between the genes driving primary resistance and those emerging during acquired resistance to anti-EGFR antibodies.
  • Mutations in KRAS, NRAS, BRAF, and alterations in ERBB2 and MET are implicated in both de novo and acquired resistance.
  • Despite genetic heterogeneity, diverse resistance mechanisms converge on common key signaling pathways.

Conclusions:

  • Molecular heterogeneity, characterized by distinct genetic alterations, significantly impacts the efficacy of anti-EGFR therapies in mCRC by causing de novo and acquired resistance.
  • Understanding the convergence of these genetically diverse resistance mechanisms on specific signaling pathways provides opportunities for therapeutic intervention.
  • This knowledge facilitates the rational design of novel therapeutic strategies to overcome resistance and improve treatment outcomes for mCRC patients.

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