Does mutated K-RAS oncogene attenuate the effect of sulindac in colon cancer chemoprevention?

Photini F.S. Rice, Kevin G. Ehrichs, Mykella S. Jones, Hwu Dau Rw Chen, Chiu-Hsieh Hsu, Edward R. Abril, Raymond B Nagle, David G. Besselsen, Jennifer K Barton, Natalia Ignatenko

Research output: Contribution to journalArticle

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Abstract

The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutant K-RAS oncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutant K-ras oncogene (K-rasG12D). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutant K-ras allele accelerated azoxymethane (AOM)-induced colon carcinogenesis in C57BL/6 mice, a strain otherwise resistant to this carcinogen. Sulindac completely prevented AOM-induced tumor formation in K-ras wild-Type (K-ras wt) animals. In K-rasG12D-mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume (P ≤ 0.01) and an increase in the number of adenoma-free mice (P = 0.04) were observed. The partial response of K-RasG12D animals to sulindac treatment was evident by the decrease in mucosal thickness (P < 0.01) and delay in progression of the precancerous aberrant crypt foci to adenomas. Molecular analyses showed significant induction in cyclooxygenase 2 (COX-2), cleaved caspase-3 (CC3), and Ki-67 expression by AOM, but not sulindac treatment, in all genotypes. Our data underscore the importance of screening for K-RAS mutations in individuals with colon polyps to provide more personalized interventions targeting mutant K-RAS signaling pathways.

Original languageEnglish (US)
Pages (from-to)16-26
Number of pages11
JournalCancer Prevention Research
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Sulindac
Chemoprevention
Oncogenes
Colonic Neoplasms
Azoxymethane
Colon
Adenoma
Carcinogenesis
Aberrant Crypt Foci
Neoplasms
Mutation
Wild Animals
ras Genes
Optical Coherence Tomography
Non-Steroidal Anti-Inflammatory Agents
Cyclooxygenase 2
Genetic Predisposition to Disease
Polyps
Tumor Burden
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Does mutated K-RAS oncogene attenuate the effect of sulindac in colon cancer chemoprevention? / Rice, Photini F.S.; Ehrichs, Kevin G.; Jones, Mykella S.; Chen, Hwu Dau Rw; Hsu, Chiu-Hsieh; Abril, Edward R.; Nagle, Raymond B; Besselsen, David G.; Barton, Jennifer K; Ignatenko, Natalia.

In: Cancer Prevention Research, Vol. 11, No. 1, 01.01.2018, p. 16-26.

Research output: Contribution to journalArticle

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