Summary
Targeted therapeutics have advanced cancer treatment, but single agent activity remains limited by de novo and acquired resistance. Combining targeted drugs is broadly seen as a way to improve treatment outcome, motivating the ongoing search for efficacious combinations. To identify synergistic targeted therapy combinations and study the impact of tumor heterogeneity on combination outcome, we systematically tested over 5,000 two drug combinations at multiple doses across a collection of 81 non-small cancer cell lines. Both known and novel synergistic combinations were identified. Strikingly, very few combinations yield synergy across the majority of cell line models. Importantly, synergism mainly arises due to sensitization of single agent resistant models, rather than further sensitize already sensitive cell lines, frequently via dual targeting of a single or two highly interconnected pathways. This drug combinations resource, the largest of its kind should help delineate new synergistic regimens by facilitating the understanding of drug synergism in cancer.
Competing Interest Statement
E.R. is a non-paid scientific consultant and cofounder of Pangea Therapeutics (www.pangeamedicine.com), which focuses on synthetic lethality based precision; however, E.R. has divested all shares and receives no salary or financial benefit from this company. C.H.B is employee of Novartis and previously received research funding from Novartis. A.F. is an employee at Scorpion Therapeutics. A.D.S. provides consultancy to Lead Pharma, Checkmate Pharmaceuticals and C-Reveal Therapeutics. D.A.F is cofounder of Tell-Bio and on the SAB of Rome Therapeutics. All other authors declare no conflict of interest.
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