Does Mutated K-RAS Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention?

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 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 oncogene ( ). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutant 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 wild-type ( wt) animals. In -mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume ( ≤ 0.01) and an increase in the number of adenoma-free mice ( = 0.04) were observed. The partial response of animals to sulindac treatment was evident by the decrease in mucosal thickness ( < 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 mutations in individuals with colon polyps to provide more personalized interventions targeting mutant signaling pathways. .

AACR White Paper: Shaping the Future of Cancer Prevention – A Roadmap for Advancing Science and Public Health

“…The clinical impact of prevention agent combinations is illustrated by the breakthrough trial sulindac and erlotinib, which reduced the occurrence of duodenal adenomas (104)(105)(106). Recent transcriptomic and other correlative science studies from this landmark-positive randomized trial in FAP identified molecular targets and innate immune pathways mediating sulindac-erlotinib suppression of duodenal polyposis; and Kras mutations attenuated sulindac efficacy in mouse models, with implications for precision prevention (107).…”

Proponent Specificity as Targeting Evolutionary Traits in Ras Isoform Mutability in Carcinogenesis

“…KRAS is the prototype molecule family as canonical player in constituting further evolution in cell adaptability and response. Screening for K-RAS gene mutations is important in patients with colon polyps to thus provide possible personalised interventions targeting mutant K-RAS signaling pathways [11] .…”