title: Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map.
abstract: There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies.
  
  
  
  Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation.
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Martins
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Alicia Y
authors.initials: AY
authors.lastname: Zhou
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Corella
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Dai
authors.initials: D
authors.lastname: Horiuchi
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Taha
authors.initials: T
authors.lastname: Rakhshandehroo
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Levin
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Johnson
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Jascur
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Mike
authors.initials: M
authors.lastname: Shales
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sorrentino
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Jaime
authors.initials: J
authors.lastname: Cheah
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.affiliation: University of California, San Francisco, San Francisco, California. bandyopadhyays@cc.ucsf.edu andrei.goga@ucsf.edu.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: University of California, San Francisco, San Francisco, California. bandyopadhyays@cc.ucsf.edu andrei.goga@ucsf.edu.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D023281:Genomics; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays