PROJECTABSTRACT Cancer invasion causes debilitating tissue and organ destruction and leads to deadly metastatic disease. As such, understanding, preventing, and treating the aberrant motility of cancer cells is a high priority cancer researchchallenge.OurlaboratoryrecentlydiscoveredthatERKanditseffectorp90RSKpromotecellmotility. These kinases are activated by common oncogenic mutations in receptor tyrosine kinases, RAS, and RAF. Interestingly, our work and that of others suggests that the p90RSK protein family members (RSK 1-4) are not equivalent in their activity on specific substrates and ability to promote invasion. Indeed, the RSKs havebeenfoundtoeitherpromoteorinhibitcellmotility,dependingonspecificcancertypes.Amajorrationale for this proposal is that the RAS?RAF pathway is currently being targeted therapeutically and clear understandingoftheroleofeachRSKfamilymemberintumorcellmotilitywouldleadtoimprovedtherapeutic designandpatientselectioninclinicaltrials.Theimmediategoalofthisapplicationistodeterminetheroleof each RSK homolog in lung cancer invasion and to identify the substrates involved in any functional specificity. We will integrate the analysis of human cell lines and murine tumor invasion models to: 1) determine which RSKs regulate non-small cell lung cancer invasion and 2) determine the mechanisms by whichrelevantRSKhomologcontributeslungcancerinvasion.Thisworkwillpavethewayforfutureeffortsto specificallytargetandinhibitRASpathwaycomponentsthatpromotetumorinvasion.
Cancer invasion is the most significant cause of cancer morbidity and mortality. This application will test the central hypothesis that the members of RSK family of protein kinases differentially regulate lung cancer invasionandprogression.
