title: Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers.
abstract: Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Kleiman
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Germany.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Krebs
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D012004:Rectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011838:Radiation-Sensitizing Agents; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins