The MAPK pathway is highly mutated in human cancers and although inhibitors have been developed to target multiple nodes, the therapeutic efficacy of these agents is still plagued by both intrinsic and acquired resistance. Our group seeks to gain a deeper understanding of MAPK pathway signaling in order to find novel ways of targeting these cancers. Our research focus covers three main aspects of the RAS-RAF-MEK-ERK signaling cascade: i) understanding basic pathway biology, ii) drug discovery, and iii) understanding resistance to pharmacological inhibition.
We are interested in examining multiple levels of regulation of the MAPK pathway including the mechanisms of activation, ERK-mediated negative feedback loops, and the regulation of signaling through the DUSP family of phosphatases. We are also investigating synthetic lethality in MAPK-mutated cancers to potentially find novel ways of inhibiting tumor cell growth. For example, a large pooled shRNA screen indicates that BRAFV600E melanoma cell lines are preferentially dependent on ERK2, rather than ERK1. These data confirm previous work in our group that further demonstrated this dependence pharmacologically, using an ATP-competitive inhibitor and drug resistant mutants of each isoform. These results are somewhat surprising given the sequence homology between ERK1 and ERK2 and the strong evidence of functional redundancy in the literature. We therefore are seeking a deeper understanding of the intricacies of ERK1 vs ERK2 signaling in cancer, which could lead to improved therapeutic approaches.