Reference Detail

Ref Type Journal Article
PMID (24798549)
Authors Maitra R, Seetharam R, Tesfa L, Augustine TA, Klampfer L, Coffey MC, Mariadason JM, Goel S
Title Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan.
Journal Oncotarget
Vol 5
Issue 9
Date 2014 May 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS mutant colorectal cancer sensitive Reolysin Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells harboring a KRAS mutation demonstrated growth inhibition, cell membrane dysruption, induction of apoptosis, and G2/M arrest in culture when treated with Reolysin (pelareorep) (PMID: 24798549). 24798549
KRAS mutant colorectal cancer sensitive Irinotecan + Reolysin Preclinical - Cell culture Actionable In a preclinical study, the combination of Reolysin (pelareorep) and Camptosar (irinotecan) resulted in a synergistic effect, demonstrating increased apoptotic activity and growth inhibition in colorectal cancer cells harboring a KRAS mutation in culture compared to either agent alone (PMID: 24798549). 24798549