Integrated CRISPR screening and drug profiling identifies combination opportunities for EGFR, ALK, and BRAF/MEK inhibitors.

Anti-tumor efficacy of targeted therapies is variable across patients and cancer types. Even in patients with initial deep response, tumors are typically not eradicated and eventually relapse. To address these challenges, we present a systematic screen for targets that limit the anti-tumor efficacy of EGFR and ALK inhibitors in non-small cell lung cancer and BRAF/MEK inhibitors in colorectal cancer. Our approach includes genome-wide CRISPR screens with or without drugs targeting the oncogenic driver ("anchor therapy"), and large-scale pairwise combination screens of anchor therapies with 351 other drugs. Interestingly, targeting of a small number of genes, including MCL1, BCL2L1, and YAP1, sensitizes multiple cell lines to the respective anchor therapy. Data from drug combination screens with EGF816 and ceritinib indicate that dasatinib and agents disrupting microtubules act synergistically across many cell lines. Finally, we show that a higher-order-combination screen with 26 selected drugs in two resistant EGFR-mutant lung cancer cell lines identified active triplet combinations.
Competing Interests: Declaration of interests All authors are or have been employees and shareholders of Novartis. During the preparation of the manuscript, W.R.S. was a Board or SAB member and equity holder in Peloton Therapeutics, Ideaya Biosciences, Civetta Therapeutics, Scorpion Therapeutics, and Bluebird Bio and has consulted for Array, Astex, Dynamo Therapeutics, Ipsen, PearlRiver Bio, Sanofi, and Servier, and receives research funding from Pfizer Pharmaceuticals, Merck, Ideaya Biosciences, Boehringer-Ingelheim, and Deerfield Management.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)