title: MEK1/2 inhibitors in the treatment of gynecologic malignancies.
abstract: Mitogen-activated protein kinases (MAPKs) are a family of ubiquitous eukaryotic signal transduction enzymes which link extracellular stimuli to intracellular gene expression pathways. While several three-tiered MAPK cascades have been elucidated in mammals, the prototypical pathway involves a network of proteins and kinases including the Rat sarcoma protein (Ras), mitogen-activated protein kinase kinase kinase (Raf or MAP3K), mitogen-activated protein kinase kinase (MEK or MAP2K), and extracellular signal regulated protein kinase (ERK or MAPK). This MAPK cascade (the Ras/Raf/MEK/ERK pathway) is a receptor tyrosine kinase mediated signaling pathway that regulates cell proliferation, cell cycle progression, and cell migration. There are multiple molecular mechanisms of interaction and activation between the upstream nodes of the Ras/Raf/MEK/ERK cascade and other cell signaling pathways, all ultimately leading to the activation of the nuclear transcription factor ERK. Important downstream targets include MEK1/2, which comprise the final step leading to ERK transcription factor activation. While multiple conduits exist to activate ERK upstream of MEK, there is little redundancy downstream. Located at this pivotal intersection between a limited number of upstream activators and its exclusive downstream targets, MEK is an appealing molecular target of novel cancer therapies. MEK inhibitors are small molecules that inhibit MEK phosphorylation by binding to a pocket adjacent to the ATP binding site, decreasing both the amount of MEK activity, and the quantity of activated ERK in the cell. Unique allosteric noncompetitive binding sites of MEK inhibitors allow specific targeting of MEK enzymes and prevent cross-activation of other serine/threonine protein kinases through the conserved ATP binding site. This paper reviews the translational evidence in favor of MEK inhibitors in cancer, their role in gynecologic malignancies, and details regarding the status of the fourteen MEK inhibitors currently being clinically tested: trametinib, selumetinib, pimasertib, refametinib, PD-0325901, MEK162, TAK733, RO5126766, WX-554, RO4987655, cobimetinib, AZD8330, MSC2015103B, and ARRY-300.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, San Antonio Military Medical Center, 3551 Roger Brooke Road, Ft. Sam, Houston, TX 78234, USA.
authors.forename: Caela R
authors.initials: CR
authors.lastname: Miller
authors.affiliation: Division of Gynecologic Oncology, Gynecologic Cancer Center of Excellence, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20814, USA.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Oliver
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member, 500 W. Thomas Road, Suite 600, Phoenix, AZ 85013, USA. Electronic address: John.farley@chw.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Farley
mesh_terms: D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: Cancer; Low grade; MAPK cascade; MEK inhibitors; Ovarian; Serous