title: Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan.
abstract: Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 inhibitor, irinotecan. Reovirus efficacy was examined in the KRAS mutant HCT116, and the isogenic KRAS WT Hke3 cell line, and in the non-malignant rat intestinal epithelial cell line. Apoptosis was determined by flow cytometry and TUNEL staining. Combination treatment with reovirus and irintoecan was investigated in 15 CRC cell lines, including the HCT116 p21 isogenic cell lines. Reovirus preferentially induced apoptosis in KRAS mutant HCT116 cells compared to its isogenic KRAS WT derivative, and in KRAS mutant IEC cells. Reovirus showed a greater degree of caspase 3 activation with PARP 1 cleavage, and preferential inhibition of p21 protein expression in KRAS mutant cells. Reovirus synergistically induced growth inhibition when combined with irinotecan. This synergy was lost upon p21 gene knock out. Reovirus preferentially induces apoptosis in KRAS mutant colon cancer cells. Reovirus and irinotecan combination therapy is synergistic, p21 mediated, and represents a novel potential treatment for patients with CRC.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, NY.
authors.forename: Radhashree
authors.initials: R
authors.lastname: Maitra
authors.forename: Raviraja
authors.initials: R
authors.lastname: Seetharam
authors.forename: Lydia
authors.initials: L
authors.lastname: Tesfa
authors.forename: Titto A
authors.initials: TA
authors.lastname: Augustine
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Coffey
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002453:Cell Cycle; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D000077146:Irinotecan; D008855:Microscopy, Electron, Scanning; D009154:Mutation / Q000235:genetics*; D050130:Oncolytic Virotherapy; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D051381:Rats; D012087:Reoviridae / Q000502:physiology*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002166:Camptothecin