This application proposes to maximize the clinical benefits of BRAF inhibitors by using combination therapies with the goal of improving the survival of patients with metastatic melanoma. Despite the recent success of BRAF inhibitors for the treatment of melanoma, responses are transient and the majority of patients develop resistance. Therefore, a major challenge is to understand, overcome, and prevent resistance to these drugs. The group has recently contributed to this endeavor by making important discoveries. Those data and studies from other groups suggest that although an array of resistance mechanisms are likely to arise in the clinical setting, most of them are associated with reactivation of the MAPK pathway and activation of PI3Kmediated survival pathways. The working hypothesis is that combination strategies that efficiently block the MAPK and PI3K pathways will result in more durable responses and likely decrease the emergence of resistance when used as upfront therapy in the right patient population. The second hypothesis is that a defined set of molecular alterations modulates therapy response. These genetic or signaling alterations can provide new targets for the development of novel combinatorial strategies aimed at killing all or nearly all of the malignant cells and thus decreasing the likelihood of tumor progression. In the first aim patients with BRAF-mutant melanoma are treated with a combination of the BRAF inhibitor vemurafenib and PX-866, an irreversible PI3K inhibitor in a phase I randomized phase II clinical trial. It is expected that the combination of vemurafenib and PX-866 will be superior to vemurafenib alone and will be well tolerated. Correlative studies will be performed to identify biomarkers of response to combined BRAF+PI3K inhibition. To this end, the genetic, genomic, and signaling profiles in pre-treatment samples will identify the molecular alterations associated with progression free survival (PFS). It is expected that the combined assessment of genetic and protein signaling profiles will allow defining robust markers of response to the combination therapy and select the patients who will benefit the most from this therapeutic regimen. In the second aim, experimental modeling of sensitivity and resistance to combined BRAF and PI3K inhibition will done. For these studies patient-derived cells in short-term cultures or propagated in immunodeficient mice without in-vitro culturing (patient-derived xenografts, PDX) will be used to identify and functionally validate mechanisms of resistance to the proposed combination therapies. This knowledge will be used to develop new strategies that can maximize the therapeutic effects of BRAF and PI3K inhibitors and can inform the design of future clinical trials. The proposed studies will provide the rationale for personalized therapy in melanoma designed to match the molecular and biologic signatures of the tumor.