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.
This phase II trial studies how well treatment that is directed by genetic testing works in patients with solid tumors or lymphomas that have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors or lymphomas.