The V Foundation MRA Young Investigator Award
Co-funded with The Melanoma Research Alliance
Although significant progress has been made treating melanoma and the recent approval of several drugs for the treatment of advanced disease, several challenges remain. For example, clinical responses are generally short-lived as tumors quickly become drug resistant and patients relapse. Moreover, tumors can develop drug resistance through a diverse number of molecular mechanisms, making the development of second-line therapies extremely daunting. Therefore, it is critical to identify therapeutic targets that are common to the majority of resistant tumors. We have recently found that a protein kinase called S6K is activated in melanomas resistant to BRAF and MEK inhibitors. Moreover, we showed that inhibition of this protein using a triple drug combination blocked the growth of resistant tumors. This provides strong rationale for establishing S6K as a novel target for melanoma therapy. Notably, S6K is a common node for most resistance pathways. We propose to investigate the role of S6K in melanoma and determine the therapeutic value of targeting this protein. Towards these goals we will determine the consequences of blocking S6K in melanoma, identify the proteins that are regulated by S6K and use this knowledge to delineate combinatorial approaches that can lead to long-term tumor remission in a large number of melanomas, including those resistant to BRAF and MEK inhibitors. We expect that the data generated by these studies can be quickly translated into new strategies aimed at maximizing the therapeutic efficacy of MAPK inhibitors in melanoma and provide actionable information that will guide the design of future clinical trials.