PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics.
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors.
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA. kiran.mahajan@moffitt.org
Kiran
K
Mahajan
Nupam P
NP
Mahajan
D002453:Cell Cycle; D049109:Cell Proliferation; D053492:Elafin / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D015533:Transcriptional Activation
D053492:Elafin; D035683:MicroRNAs; C506806:PI3 protein, human; D051058:Oncogene Protein v-akt