%0 Journal Article %A Jorge Gómez Tejeda Zañudo %A Pingping Mao %A Clara Alcon %A Kailey J. Kowalski %A Gabriela N. Johnson %A Guotai Xu %A José Baselga %A Maurizio Scaltriti %A Anthony Letai %A Joan Montero %A Reka Albert %A Nikhil Wagle %T Cell line-specific network models of ER+ breast cancer identify PI3Kα inhibitor sensitivity factors and drug combinations %D 2020 %R 10.1101/2020.08.25.261370 %J bioRxiv %P 2020.08.25.261370 %X Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. A promising approach to tackle the cancer drug resistance problem is to build mechanistic mathematical models of the signaling network of cancer cells, and explicitly model the dynamics of information flow through this network under distinct genetic conditions and in response to perturbations.In this work, we used a network-based mathematical model to identify sensitivity factors and drug combinations for the PI3Kα inhibitor alpelisib, which was recently approved for ER+ PIK3CA mutant breast cancer. We experimentally validated the model-predicted efficacious combination of alpelisib and BH3 mimetics (e.g. MCL1 inhibitors) in ER+ breast cancer cell lines. We also experimentally validated the reduced sensitivity to alpelisib caused by FOXO3 knockdown, which is a novel potential resistance mechanism. Our experimental results showed cell line-specific sensitivity to the combination of alpelisib and BH3 mimetics, which was driven by the choice of BH3 mimetics. We find that cell lines were sensitive to the addition of either MCL1 inhibitor s63845 alone or in combination with BCL-XL/BCL-2 inhibitor navitoclax, and that the need for the combination of both BH3 mimetics was predicted by the expression of BCL-XL. Based on these results, we developed cell line-specific network models that are able to recapitulate the observed differential response to alpelisib and BH3 mimetics, and also incorporate the most recent knowledge on resistance and response to PI3Kα inhibitors.Overall, we present an approach for the development, experimental testing, and refining of mathematical models, which we apply to the context of PI3Kα inhibitor drug resistance in breast cancer. Our approach predicted and validated PI3Kα inhibitor sensitivity factors (FOXO3 knockdown) and drug combinations (BH3 mimetics), and illustrates that network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.Competing Interest StatementP.M. is an employee of Bluebird bio. J.B. is an employee of AstraZeneca; is on the Board of Directors of Foghorn; and is a past board member of Varian Medical Systems, Bristol‐Myers Squibb, Grail, Aura Biosciences, and Infinity Pharmaceuticals. He has performed consulting and/or advisory work for Grail, PMV Pharma, ApoGen, Juno, Eli Lilly, Seragon, Novartis, and Northern Biologics. He has stock or other ownership interests in PMV Pharma, Grail, Juno, Varian, Foghorn, Aura, Infinity Pharmaceuticals, and ApoGen, as well as Tango and Venthera, of which he is a cofounder. He has previously received honoraria or travel expenses from Roche, Novartis, and Eli Lilly. J.B. is an employee of AstraZeneca, which is currently developing capivasertib, an AKT inhibitor. J.B. is a past board member of Infinity Pharmaceuticals, which markets duvelisib and IPI-549. J.B. has been a paid consultant and/or advisor for Novartis, which markets alpelisib, buparlisib, and everolimus. J.B. has stock or other ownership interests in Venthera (of which he is a cofounder), which is developing topical PI3K inhibitors for dermatological conditions. Companies that have developed or are developing PI3K inhibitors, for which coauthors on this study have a disclosure, include Novartis, AstraZeneca, Eli Lilly, Roche, Infinity Pharmaceuticals, and Venthera. J.B. is an inventor on a patent application (PCT/US2019/047879) submitted by MSKCC that is related to the use of multiple PIK3CA mutations as a biomarker for clinical response to PI3K inhibitors. M.S. is on the scientific advisory board of Menarini Ricerche and the Bioscience Institute; has received research funds from Puma Biotechnology, Daiichi-Sankio, Targimmune, Immunomedics, and Menarini Ricerche; and is a cofounder of Medendi.org. M.S. has received research funds from Menarini Ricerche, which markets MEN1611. A.G.L. reports consulting for AbbVie, sponsored research by Novartis, AbbVie, Astra-Zeneca, and being a co-founder of Flash Therapeutics and Vivid Bioscience. J.M. reports previous consulting for Vivid Biosciences and Oncoheroes Biosciences. N.W. reports the following prior relationships: Foundation Medicine (consultant, stockholder), Novartis (consultant, grant support, advisory board). N.W. reports the following current relationships: Puma Biotechnologies (grant support), Eli Lilly (consultant/advisory board), Section 32 (scientific advisory board), Relay Therapeutics (scientific advisory board, stockholder). No potential conflicts of interests were disclosed by the other authors. %U https://www.biorxiv.org/content/biorxiv/early/2020/12/13/2020.08.25.261370.full.pdf