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Review
. 2024 Apr 22:15:1398419.
doi: 10.3389/fphar.2024.1398419. eCollection 2024.

Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road

Alejandro Ríos-Hoyo  1 , Xavier Monzonís  2 , Joana Vidal  2 , Jenniffer Linares  2 , Clara Montagut  2
Affiliations
Review

Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road

Alejandro Ríos-Hoyo et al. Front Pharmacol. .

Abstract

Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.

Keywords: CtDNA; acquired resistance; anti-EGFR; anti-EGFR rechallenge; clonal dynamics; colorectal cancer; liquid biopsy; tumor heterogeneity.

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Conflict of interest statement

AR-H reports traveling accommodations from Novartis and Roche. CM reports scientific consultancy role, travel grants or research grants past 5 years from Amgen, Biocartis, BMS, Guardant-Health, Merck-Serono, Roche, Sanofi Aventis, and SeaGen. JV reports personal fees and other support from Merck and personal fees from Amgen, Sanofi, and BMS outside the submitted work. The remaining authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Molecular mechanisms of acquired resistance to anti-EGFR therapies.
FIGURE 2
FIGURE 2
Tumor heterogeneity and clonal dynamics in metastatic CRC. (A) Multiple metastatic lesions showing the presence of various subclones within the tumor, each with different genomic alterations. (B) Clonal dynamics representing an original dominant clone, responding to treatment, and the rise of other treatment resistant clones.
FIGURE 3
FIGURE 3
Anti-EGFR treatment of RAS/BRAF wt mCRC according to clonal dynamics assessed in ctDNA (A) Treatment naïve CRC with a predominant clone of anti-EGFR sensitive cancer cells (B) Tumor response to first-line treatment with anti-EGFR therapy. (C) Tumor progression and emergence of sub-clones of resistance to anti-EGFR therapy. (D) Decay of the anti-EGFR resistant clones with second-line treatment without anti-EGFR therapy. (E) Tumor progression. (F) Tumor response to third-line anti-EGFR rechallenge.
See this image and copyright information in PMC

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