title: Targeting protein kinase-b3 (akt3) signaling in melanoma.
abstract: Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35-70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available. Areas covered: This review provides a brief introduction of the PI3K-Akt signaling pathway and its role in melanoma development. In addition, the functional role of key Akt pathway members such as PRAS40, GSK3 kinases, WEE1 kinase in melanoma development are discussed together with strategies to modulate these targets. Efficacy and safety of Akt inhibitors is also discussed. Finally, the mechanism(s) through which Akt leads to drug resistance is discussed in this expert opinion review. Expert opinion: Even though Akt play key roles in melanoma tumor progression, cell survival and drug resistance, many gaps still exist that require further understanding of Akt functions, especially in the (a) metastatic spread; (b) circulating melanoma cells survival; and
authors.affiliation: a Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry , JSS Medical College, Jagadguru Sri Shivarathreeshwara University (Accredited 'A' Grade by NAAC and Ranked 35 by National Institutional Ranking Framework (NIRF)-2015, Ministry of Human Resource Development, Government of India) , Mysuru , India.
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.affiliation: b Department of Pharmacology , The Pennsylvania State University College of Medicine , Hershey , PA , USA.|c Department of Pathology , The Pennsylvania State University College of Medicine , Hershey , PA , USA.|d Department of Dermatology , The Pennsylvania State University College of Medicine , Hershey , PA , USA.|e Department of Surgery , The Pennsylvania State University College of Medicine , Hershey , PA , USA.|f The Melanoma Center , The Pennsylvania State University College of Medicine , Hershey , PA , USA.|g The Melanoma Therapeutics Program , The Pennsylvania State University College of Medicine , Hershey , PA , USA.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT3; Akt inhibitors; PI3K; PRAS40; PTEN; drug resistance; melanoma