Abstract C178: TAS-117, a highly potent and selective non-ATP competitive inhibitor of AKT, demonstrates a toxicity profile with manageable hyperglycemia in rats.
Authors: Moriyama Kenji , Yamaguchi Masahiro , Sugimoto Shigeo , Matsumura Hirofumi , Ninomiya Fumiko , Besshi Kazuhiko , Morita Fumio , Hayashi Taiji , Fujita Ryouto , Fukushima Hiroto , Shimomura Toshiyasu , Yonekura Kazuhiko , Utsugi Teruhiro 
Published: August 2014

Background: TAS-117 is a small molecule which inhibits the PI3K-AKT-mTOR signaling pathway, a critical regulator of cell survival, by stimulating cell proliferation and inhibiting apoptosis. One of the most notable AKT-related adverse events is hyperglycemia which has been a dose limiting toxicity (DLT) in some clinical trials. We elucidate the time-dependent changes of hyperglycemia induced by TAS-117 and try an approach to manage the hyperglycemia in the present study.

Materials and Methods: TAS-117 was orally administered to male rats repeatedly for 2 weeks (QD) to evaluate the toxicities of TAS-117. Blood glucose and insulin were measured continuously for 24 hours on the first and last day of dosing. Water intake recording and urinalysis were also performed to monitor for diabetes-related findings. Then, we treated the rats with varying anti-diabetic agents, gliclazide, mitiglinide calcium hydrate, pioglitazone hydrochloride, and metformin hydrochloride, in order to ameliorate the observed diabetes-like effects.

Results: In continuous monitoring of blood glucose levels, TAS-117 induced transient elevation of blood glucose and insulin following daily oral administration. The peak level of blood glucose was observed between 4 and/or 8 hours after dosing. TAS-117-induced hyperglycemia reverted to baseline by 24 hours after dosing. Blood insulin levels correlatively increased and decreased with changes in blood glucose levels. Additionally, TAS-117 induced diabetes-like changes including body-weight-gain suppression, increases in water intake, urine volume, and urine glucose level were observed. These changes were deemed to be related to the hyperglycemia caused by TAS-117. However, the hyperglycemic effects of TAS-117 were most ameliorated by one of the anti-diabetic agents given, Metformin hydrochloride, an inhibitor of gluconeogenesis. The peak in blood glucose levels in Metformin medicated rats was suppressed up to 31% as compared with that in TAS-117 alone treated rats.

Conclusion: TAS-117’s main toxic effects in rats were diabetes-like, including hyperglycemia and blood insulin elevation due to TAS-117’s dysregulation of carbohydrate metabolism. However, these adverse effects were transient and reversible and were controlled by a particular class of anti-diabetic agent. Therefore, TAS-117 has the potential to be administered on a daily schedule without inducing clinically significant hyperglycemia.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C178.

Citation Format: Kenji Moriyama, Masahiro Yamaguchi, Shigeo Sugimoto, Hirofumi Matsumura, Fumiko Ninomiya, Kazuhiko Besshi, Fumio Morita, Taiji Hayashi, Ryouto Fujita, Hiroto Fukushima, Toshiyasu Shimomura, Kazuhiko Yonekura, Teruhiro Utsugi. TAS-117, a highly potent and selective non-ATP competitive inhibitor of AKT, demonstrates a toxicity profile with manageable hyperglycemia in rats. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C178.