Primary Prevention and Interception Studies in RAS-Mutated Tumor Models Employing Small Molecules or Vaccines

Therapeutic targeting of RAS-mutated cancers is diffiprevented the development of virtually all pancreatic cult, whereas prevention or interception (treatment before tumors in transgenic mice. In the N-nitroso-N-methy- or in the presence of preinvasive lesions) preclinically has lurea-induced estrogen receptor–positive rat breast model proven easier. In the A/J mouse lung model, where dif-(50% HRAS mutations) various selective estrogen receptor ferent carcinogens induce tumors with different KRAS modulators, aromatase inhibitors, EGFR inhibitors, and mutations, glucocorticoids and retinoid X receptor (RXR) RXR agonists are profoundly effective in prevention and agonists are effective agents in prevention and intercepinterception of tumors with wild-type or mutant HRAS, tion studies, irrespective of specific KRAS mutations. In while the farnesyltransferase inhibitor tipifarnib preferenrat azoxymethane-induced colon tumors (45% KRAS tially inhibits HRAS-mutant breast tumors. Thus, many mutations), cyclooxygenase 1/2 inhibitors and difluoroagents not known to specifically inhibit the RAS pathway, methylornithine are effective in preventing or intercepting are effective in an organ specific manner in preventing or KRAS-mutated or wild-type tumors. In two KRAS-mutant intercepting RAS-mutated tumors. Finally, we discuss an pancreatic models multiple COX 1/2 inhibitors are effective. alternative prevention and interception approach, employ-Furthermore, combining a COX and an EGFR inhibitor ing vaccines to target KRAS.