Mitogen-Activated Protein Kinase (MAPK) Driven Rare Gynecologic Cancers and Evolving Therapeutic Targets

The MAPK cascade is a critical pathway involved in cancer cell survival as well as resistance to drug therapy. Phosphorylation of ERK1 and ERK2, the final effectors of the MAPK pathway, results in activation of multiple substrates that are responsible for cellular proliferation, differentiation, survival and migration[1]. Many oncogenic driver mutations have been identified in genes upstream of MAPK/ERK, including mutations in KRASand V600EBRAF,which can lead to overactivation of the MAPK/ERK pathway. This signaling cascade, particularly its intracellular components, RAF and MEK, have been a major focus for drug discovery efforts during the past decade, and small molecule inhibitors of both RAF and MEK have progressed to clinical evaluations and registration in multiple cancers[2].