Effective drug combinations in breast, colon and pancreatic cancer cells

Patricia Jaaks, Elizabeth A. Coker, Daniel J. Vis, Olivia Edwards, Emma F. Carpenter, Simonetta M. Leto, Lisa Dwane, Francesco Sassi, Howard Lightfoot, Syd Barthorpe, Dieudonne Meer, Wanjuan Yang, Alexandra Beck, Tatiana Mironenko, Caitlin Hall, James Hall, Iman Mali, Laura Richardson, Charlotte Tolley, James Morris, Frances Thomas, Ermira Lleshi, Nanne Aben, Cyril H. Benes, Andrea Bertotti, Livio Trusolino, Lodewyk Wessels and Mathew J. Garnett ()
Additional contact information
Patricia Jaaks: Wellcome Sanger Institute
Elizabeth A. Coker: Wellcome Sanger Institute
Daniel J. Vis: The Netherlands Cancer Institute
Olivia Edwards: Wellcome Sanger Institute
Emma F. Carpenter: Wellcome Sanger Institute
Simonetta M. Leto: Candiolo Cancer Institute, FPO–IRCCS
Lisa Dwane: Wellcome Sanger Institute
Francesco Sassi: Candiolo Cancer Institute, FPO–IRCCS
Howard Lightfoot: Wellcome Sanger Institute
Syd Barthorpe: Wellcome Sanger Institute
Dieudonne Meer: Wellcome Sanger Institute
Wanjuan Yang: Wellcome Sanger Institute
Alexandra Beck: Wellcome Sanger Institute
Tatiana Mironenko: Wellcome Sanger Institute
Caitlin Hall: Wellcome Sanger Institute
James Hall: Wellcome Sanger Institute
Iman Mali: Wellcome Sanger Institute
Laura Richardson: Wellcome Sanger Institute
Charlotte Tolley: Wellcome Sanger Institute
James Morris: Wellcome Sanger Institute
Frances Thomas: Wellcome Sanger Institute
Ermira Lleshi: Wellcome Sanger Institute
Nanne Aben: The Netherlands Cancer Institute
Cyril H. Benes: Harvard Medical School
Andrea Bertotti: Candiolo Cancer Institute, FPO–IRCCS
Livio Trusolino: Candiolo Cancer Institute, FPO–IRCCS
Lodewyk Wessels: The Netherlands Cancer Institute
Mathew J. Garnett: Wellcome Sanger Institute

Nature, 2022, vol. 603, issue 7899, 166-173

Abstract: Abstract Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS–TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

Date: 2022
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DOI: 10.1038/s41586-022-04437-2

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