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ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer

Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In add...

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Detalles Bibliográficos
Autores principales: Johnson, Radia M., Qu, Xueping, Lin, Chu-Fang, Huw, Ling-Yuh, Venkatanarayan, Avinashnarayan, Sokol, Ethan, Ou, Fang-Shu, Ihuegbu, Nnamdi, Zill, Oliver A., Kabbarah, Omar, Wang, Lisa, Bourgon, Richard, de Sousa e Melo, Felipe, Bolen, Chris, Daemen, Anneleen, Venook, Alan P., Innocenti, Federico, Lenz, Heinz-Josef, Bais, Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9482920/
https://www.ncbi.nlm.nih.gov/pubmed/36117191
http://dx.doi.org/10.1038/s41467-022-33172-5
Descripción
Sumario:Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.