Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC.

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Publication Details

Journal
Nature Communications
Published
2025-05-09
DOI
https://doi.org/10.1038/s41467-025-59588-3
Citations
11
Primary Topic
Colorectal Cancer Treatments and Studies
Type
article
Field-Weighted Citation Impact
11.50

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article

Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer

Matthew J. Wongchenko, Carlos Bais, Cathy Eng, Yi Shi et al.
11 citations
Nature Communications
Colorectal Cancer Treatments and Studies
11.50
article

Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer

Matthew J. Wongchenko, Carlos Bais, Cathy Eng, Yi Shi, Smruthy Sivakumar, Ethan Sokol, Johanna C. Bendell, Fortunato Ciardiello, Andrew Mancini, David S. Shames, Radia Marie Johnson, Felipe de Sousa e Melo, Habib Hamidi, Xueping Qu, Eva Lin, Yibing Yan, Bünyamin Kaplan, Tae-Won Kim
article en
11 citations

Abstract

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC.

Nature CommunicationsVol. 16(1)
The University of Texas MD Anderson Cancer Center (US), Asan Medical Center (KR), University of Ulsan (KR), Sarah Cannon (US), Azienda Ospedaliera Universitaria Università degli Studi della Campania Luigi Vanvitelli (IT), Tennessee Oncology (US), Eos Neuroscience (United States) (US), Foundation Medicine (United States)
F. Hoffmann-La Roche, Genentech, Foundation Medicine
Good health and well-being
Openalex Percentile: Top 1%
Colorectal Cancer Treatments and Studies
11.50
DOIOpen Access PDFOpenAlex
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