Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors

Molecular Cancer Therapeutics
Barry R DaviesEmma L Jenkins

Abstract

AKT1(E17K) mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1(E17K) mutation is not known. Expression of exogenous copies of AKT1(E17K) in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1(E17K) mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1(E17K) mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1(E17K) and FGFR3(Y373C) mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor re...Continue Reading

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Citations

May 22, 2016·Clinical Neurology and Neurosurgery·Anastasia ZikouMaria I Argyropoulou
Nov 26, 2016·Journal of Neurosurgery·Matthew R StricklandFred G Barker
Dec 10, 2017·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Tatsunori ShimoiKenji Tamura
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Dec 12, 2020·Molecular Cancer Research : MCR·Sizhi Paul GaoDavid B Solit

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