GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.
OBJECTIVE
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.


METHODS
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 TgMISIIR-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.


CONCLUSIONS
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.
Altomare
Deborah A
DA
Women's Cancer, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Zhang
Lili
L
Deng
Jing
J
Di Cristofano
Antonio
A
Klein-Szanto
Andres J
AJ
Kumar
Rakesh
R
Testa
Joseph R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C528328:GSK690693; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D051058:Oncogene Protein v-akt