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

Radia M. Johnson; Xueping Qu; Chu Fang Lin; Ling Yuh Huw; Avinashnarayan Venkatanarayan; Ethan Sokol; Fang Shu Ou; Nnamdi Ihuegbu; Oliver A. Zill; Omar Kabbarah; Lisa Wang; Richard Bourgon; Felipe de Sousa e Melo; Chris Bolen; Anneleen Daemen; Alan P. Venook; Federico Innocenti; Heinz Josef Lenz; Carlos Bais

doi:10.1038/s41467-022-33172-5

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

Radia M. Johnson, Xueping Qu, Chu Fang Lin, Ling Yuh Huw, Avinashnarayan Venkatanarayan, Ethan Sokol, Fang Shu Ou, Nnamdi Ihuegbu, Oliver A. Zill, Omar Kabbarah, Lisa Wang, Richard Bourgon, Felipe de Sousa e Melo, Chris Bolen, Anneleen Daemen, Alan P. Venook, Federico Innocenti, Heinz Josef Lenz, Carlos Bais

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	5478
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33172-5
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Johnson, R. M., Qu, X., Lin, C. F., Huw, L. Y., Venkatanarayan, A., Sokol, E., Ou, F. S., Ihuegbu, N., Zill, O. A., Kabbarah, O., Wang, L., Bourgon, R., de Sousa e Melo, F., Bolen, C., Daemen, A., Venook, A. P., Innocenti, F., Lenz, H. J., & Bais, C. (2022). ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer. Nature communications, 13(1), Article 5478. https://doi.org/10.1038/s41467-022-33172-5

Johnson, RM, Qu, X, Lin, CF, Huw, LY, Venkatanarayan, A, Sokol, E, Ou, FS, Ihuegbu, N, Zill, OA, Kabbarah, O, Wang, L, Bourgon, R, de Sousa e Melo, F, Bolen, C, Daemen, A, Venook, AP, Innocenti, F, Lenz, HJ & Bais, C 2022, 'ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer', Nature communications, vol. 13, no. 1, 5478. https://doi.org/10.1038/s41467-022-33172-5

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title = "ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer",

abstract = "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.",

author = "Johnson, {Radia M.} and Xueping Qu and Lin, {Chu Fang} and Huw, {Ling Yuh} and Avinashnarayan Venkatanarayan and Ethan Sokol and Ou, {Fang Shu} and Nnamdi Ihuegbu and Zill, {Oliver A.} and Omar Kabbarah and Lisa Wang and Richard Bourgon and {de Sousa e Melo}, Felipe and Chris Bolen and Anneleen Daemen and Venook, {Alan P.} and Federico Innocenti and Lenz, {Heinz Josef} and Carlos Bais",

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AU - Johnson, Radia M.

AU - Qu, Xueping

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AU - Huw, Ling Yuh

AU - Venkatanarayan, Avinashnarayan

AU - Sokol, Ethan

AU - Ou, Fang Shu

AU - Ihuegbu, Nnamdi

AU - Zill, Oliver A.

AU - Kabbarah, Omar

AU - Wang, Lisa

AU - Bourgon, Richard

AU - de Sousa e Melo, Felipe

AU - Bolen, Chris

AU - Daemen, Anneleen

AU - Venook, Alan P.

AU - Innocenti, Federico

AU - Lenz, Heinz Josef

AU - Bais, Carlos

PY - 2022/12

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N2 - 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.

AB - 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.

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

Abstract

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