The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions. Activation of the pathway can result from activation/mutations of the upstream receptor tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and MEK. Upon activation, RAF acts as the MAPK kinase kinase and activates MAPKK (MEK1/2), which in turn catalyze activation of the effectors ERK1/ERK2. Once activated, ERK1/2 translocate into the nucleus and phosphorylate a number of effector proteins and transcriptional factors that regulate cell proliferation, motility, differentiation, and survival.
Neurofibromatosis 1 (NF1) produces the protein product neurofibromin. Neurofibromatosis type 1 is an autosomal dominant familial cancer predisposition syndrome, which occurs as a result of inactivating mutations in NF1. Somatic NF1 mutations or deletions have also been identified in multiple cancer subtypes in a range from 1.8-14.3% of tumors Neurofibromin is a tumor suppressor that regulates the downstream RAS/RAF/MEK/ERK pathway. Preclinical data have demonstrated that tumors with NF1 inactivation are sensitive to MEK inhibitors . The antitumor activity of MEK inhibition in NF1 mutant tumors will be tested in this subprotocol of the MATCH study.
NCG 275215 S1