title: Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer.
abstract: ATP-competitive mammalian target of rapamycin (mTOR) inhibitors are in early phase clinical trials. These novel targeted agents, including PP242, are mechanistically distinct from the allosteric, partial mTOR inhibitor, rapamycin. The goal of this study was to evaluate how PP242 best combines with standard chemotherapies for colorectal cancer (CRC), and which subsets of patients are most likely to benefit. The combination index for PP242 plus 5-fluorouracil, oxaliplatin, or irinotecan was determined in CRC cell lines with different mutational backgrounds. In KRAS mutant CRC cell lines, sensitivity to PP242 increases with co-mutation of PIK3CA. Mutation of p53 predicts resistance to chemotherapy, but not PP242. Efficacy of PP242 was comparable to that of standard chemotherapies over the dose range tested. Sensitivity or resistance to PP242 dictates relative synergy or antagonism, respectively, when PP242 is combined with 5-fluorouracil. The same trend exists for PP242 + oxaliplatin, but with a narrower dynamic range. Conversely potency of PP242 and the combination index for PP242 + irinotecan were unrelated, but synergy exists across all dose levels in PP242 and irinotecan sensitive, p53 wild-type cell lines. Overall, our in vitro analysis predicts that mutational status can be used to rank sensitivity to PP242 and standard chemotherapies. Single agent potency can in turn be used to predict the combination index in a drug-specific manner. Our data suggest a clinical trial to determine whether ATP-competitive mTOR inhibitors provide benefit in combination with standard chemotherapies for patients with PIK3CA mutant metastatic CRC, stratified by the presence or absence of KRAS co-mutation.
authors.affiliation: Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. chloe.atreya@gmail.com
authors.forename: Chloe E
authors.initials: CE
authors.lastname: Atreya
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ducker
authors.forename: Morris E
authors.initials: ME
authors.lastname: Feldman
authors.forename: Emily K
authors.initials: EK
authors.lastname: Bergsland
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D000077146:Irinotecan; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011687:Purines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007211:Indoles; C117307:KRAS protein, human; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; C503859:PI3KCA protein, human; D011518:Proto-Oncogene Proteins; D011687:Purines; D014157:Transcription Factors; D000077150:Oxaliplatin; D000077146:Irinotecan; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C572919:PP242; D005472:Fluorouracil; D002166:Camptothecin