mk-2206 and Uterine-Cervical-Neoplasms

MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors.. Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1.. Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months.. MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Female; Gastrointestinal Neoplasms; Heterocyclic Compounds, 3-Ring; Humans; Leiomyosarcoma; Male; Middle Aged; Proto-Oncogene Proteins c-akt; Uterine Cervical Neoplasms

PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.. Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay.. Activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.. The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Cyclohexanones; Female; Glucose; Heterocyclic Compounds, 3-Ring; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms