title: KRAS mutant colorectal cancer gene signatures identified angiotensin II receptor blockers as potential therapies.
abstract: Colorectal cancer (CRC) is a life-threatening disease with high prevalence and mortality worldwide. The KRAS oncogene is mutated in approximately 40% of CRCs. While antibody based EGFR inhibitors (cetuximab and panitumumab) represent a major treatment strategy for advanced KRAS wild type (KRAS-WT) CRCs, there still remains no effective therapeutic course for advanced KRAS mutant (KRAS-MT) CRC patients.In this study, we employed a novel and comprehensive approach of gene expression connectivity mapping (GECM) to identify candidate compounds to target KRAS-MT tumors. We first created a combined KRAS-MT gene signature with 248 ranked significant genes using 677 CRC clinical samples. A series of 248 sub-signatures was then created containing an increasing number of the top ranked genes. As an input to GECM analysis, each sub-signature was translated into a statistically significant therapeutic drugs list, which was finally combined to obtain a single list of significant drugs.We identify four antihypertensive angiotensin II receptor blockers (ARBs) within the top 30 significant drugs indicating that these drugs have a mechanism of action that can alter the KRAS-MT CRC oncogenic signaling. A hypergeometric test (p-value = 6.57 × 10-6) confirmed that ARBs are significantly enriched in our results. These findings support the hypothesis that ARB antihypertensive drugs may directly block KRAS signaling resulting in improvement in patient outcome or, through a reversion to a KRAS wild-type phenotype, improve the response to anti-EGFR treatment. Antihypertensive angiotensin II receptor blockers are therefore worth further investigation as potential therapeutic candidates in this difficult category of advanced colorectal cancers.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Dunne
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: O'Reilly
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Li
authors.affiliation: Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, C-TRIC, Londonderry, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bjourson
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Darragh G
authors.initials: DG
authors.lastname: McArt
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hamilton
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.|Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, C-TRIC, Londonderry, UK.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D055808:Drug Discovery; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D009154:Mutation; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D000970:Antineoplastic Agents; D018631:ras Proteins
keywords: FDA approved drugs; KRAS mutation; colorectal cancer; connectivity mapping; differentially expressed genes