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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Activating mutations in AKT1, specifically AKT1(E17K), are found in various solid tumors.
• While AKT1(E17K) transforms rodent cells, its oncogenic potential and therapeutic targeting in human cancers remain under investigation.
• The efficacy of AKT inhibitors in human tumors harboring endogenous AKT1(E17K) mutations is not well-established.

Purpose of the Study:

• To investigate the oncogenic role of AKT1(E17K) in breast epithelial cells.
• To evaluate the therapeutic efficacy of AKT inhibitors against tumors with AKT1(E17K) mutations.
• To explore the potential of combination therapies for tumors with co-occurring mutations.

Main Methods:

• Exogenous expression of AKT1(E17K) in MCF10A cells to assess cellular transformation and in vivo tumor formation.
• Treatment of breast cancer explants and MGH-U3 bladder cancer xenografts with AKT inhibitors (MK-2206, AZD5363) and/or FGFR inhibitor (AZD4547).
• Analysis of a Phase I clinical study involving AZD5363 in cancer patients with AKT1(E17K) mutations.

Main Results:

• Expression of AKT1(E17K) increased AKT phosphorylation, colony formation, and tumor growth in mice, effects reversed by AKT inhibitors.
• Both allosteric and catalytic AKT inhibitors significantly inhibited growth in breast cancer models with AKT1(E17K).
• Phase I study showed partial responses to AZD5363 in patients with AKT1(E17K)-mutated breast and ovarian cancers. AZD5363 combined with AZD4547 showed tumor regression in bladder cancer xenografts with AKT1(E17K) and FGFR3(Y373C) mutations.

Conclusions:

• Tumors harboring the AKT1(E17K) mutation represent a validated therapeutic target for AKT inhibitors.
• AKT inhibitors demonstrate clinical activity in patients with AKT1(E17K)-mutated cancers.
• Combination therapy with other targeted agents may be necessary for tumors with multiple oncogenic driver mutations, such as AKT1(E17K) and FGFR3(Y373C).