Reference Detail

Ref Type

Journal Article

PMID

(24978597)

Authors

Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, Rouse MB, Rabindran SK, Heerding DA, Kumar R

Title

Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	9	6	2014	e100880	PLoS One

URL

Abstract Text

Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Uprosertib	Uprosertib	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Uprosertib		GSK2141795\|GSK-2141795\|GSK 2141795	Akt Inhibitor (Pan) 21 AKT Inhibitor (Pan) - ATP competitive 7	Uprosertib (GSK2141795) is an ATP-competitive inhibitor of AKT, which leads to inhibition of PI3K/AKT signaling potentially resulting in inhibition of cell proliferation and anti-tumor growth (PMID: 24978597, PMID: 32062691).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA act mut	Advanced Solid Tumor	sensitive	Afuresertib	Preclinical	Actionable	In a preclinical study, various tumor cell lines harboring PI3KCA activating mutations demonstrated increased sensitivity to Afuresertib (GSK2110183) in cultured cells (PMID: 24978597).	24978597