A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

• DOI: 10.1016/j.celrep.2017.07.006
• Publication Date: 2017-07-25T18:46:08Z
• Authors: Grace R. Anderson; Peter S. Winter; Kevin H. Lin; Daniel P. Nussbaum; Merve Cakir; Elizabeth M. Stein; Ryan S. Soderquist; Lorin Crawford; Jim C. Leeds; Rachel Newcomb; Priya Stepp; Catherine Yip; Suzanne E. Wardell; Jennifer P. Tingley; Moiez Ali; Mengmeng Xu; Meagan Ryan; Shannon J. McCall; Autumn J. McRee; Christopher M. Co...; Channing J. Der; Kris C. Wood
• Keywords: 0303 health sciences; drug resistance; QH301-705.5; apoptosis; Apoptosis; PIK3CA; synthetic lethality; 3. Good health; pooled screening; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Cell Line, Tumor; Mutation; KRAS; Humans; BIM; Clustered Regularly Interspaced Short Palindromic Repeats; Biology (General); Colorectal Neoplasms; CRISPR/Cas9; SRC; Signal Transduction

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.