GSK690693 Delays Tumor Onset and Progression in Genetically Defined Mouse Models Expressing Activated Akt

Abstract

Purpose: Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693.Experimental Design: We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten +/− knockout mice that exhibit endometrial tumors, and TgMI-SIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies.Results: GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation.Conclusion: These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression. Clin Cancer Res; 16(2); 486-96.

NF-κB and AKT signaling prevent DNA damage in transformed pre-B cells by suppressing RAG1/2 expression and activity

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PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…GSK690693 is found to be sensitive against the sixty-two hematologic tumor cell lines, including ALL, AML, CLL, CML, Burkitt's lymphoma, non-Hodgkin's lymphoma and Hodgkin's lymphoma cell lines, and induces apoptosis and growth inhibition [160] . Recent studies using preclinical models suggest that GSK690693 had its greatest efficacy in delaying tumor progression in tumors and tumor derived cell lines with a high degree of Akt activation, including those with myristoylated constitutively active Akt or with PTEN loss [161] . However, in vivo testing of preclinical models suggests that GSK690693 exerts a moderate activity in solid tumor and ALL xenograft models [162] .…”

Akt inhibitors in clinical development for the treatment of cancer

“…67 Although GSK690693 appeared to delay tumor growth irrespective of Akt activation status, it was noted to be particularly effective in MyrAkt2 mice expressing a constitutively activated, membrane bound form of Akt. 68 Despite these encouraging preclinical data, clinical development of the agent was halted due to interim results from a phase I trial testing an IV formulation of the agent. 69 No published reports describe the rationale for terminating the study; however, an interim report does cite transient drug-related hyperglycemia as an associated side effect.…”