title: Stamping out RAF and MEK1/2 to inhibit the ERK1/2 pathway: an emerging threat to anticancer therapy.
abstract: The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mandal
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Becker
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Strebhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2