Abstract 4696: Combining AZD8186, an inhibitor of PI3Kbeta, with inhibitors of PI3Kalpha and mTORC1/2 gives comprehensive pathway suppression and enhanced antitumor activity in PTEN null tumors

Abstract

Abstract The PI3K pathway drives the progression of many human tumours via mutation of PI3KCA or AKT, loss of tumour suppressors PTEN or TSC1/2, or over-expression of receptor tyrosine kinases, such as EGFR, Erb2, or IGFR. Targeting the PI3K pathway has been challenging due to toxicities with the first generation compounds. Despite this, positive clinical activity has been achieved, particularly in combination. Maximum benefit with inhibitors of the PI3K pathway is likely to be in combination, with agents that target other pathways, or PI3K signalling at different nodes. In cells, AZD8186 inhibits PI3Kbeta- and PI3Kdelta-dependent phosphorylation of AKT with IC50s of 3nM and 17nM respectively. Tumour cells can become dependent on PI3Kbeta when they lose PTEN protein function. PI3Kbeta inhibitors are differentiated from PI3Kalpha, mTOR and AKT inhibitors as they do not modulate peripheral glucose and other aspects of the canonical PI3Kalpha signalling pathway. Therefore in tumours where PI3Kbeta is activated it may be possible to combine AZD8186 with other inhibitors of the PI3K pathway to achieve comprehensive pathway suppression. Delivering comprehensive pathway suppression has become critically important with the realisation that resistance to the PI3K inhibitors can occur through feedback-mediated or mutation-mediated reactivation of the pathway through alternate PI3K isoforms. We have explored intra-pathway combinations of AZD8186 with inhibitors of PI3Kalpha (AZD8835 and BYL719) and mTOR (AZD2014 and everolimus) in PTEN protein deficient models. In particular, combining AZD8186 with inhibitors of mTOR increased efficacy across a range of tumour models. In TNBC (HCC-70) or renal (786-0) xenograft models, combined inhibition resulted in tumour regression. The degree of tumour regression was influenced by dose and schedule. For example, intermittent dosing of AZD8186 with continuous AZD2014 regressed 786-0 tumours by between 38% and 82%, while HCC70 showed a 21% regression. Tumour regressions were also observed when AZD8186 and AZD2014 were dosed intermittently, a 5 day on AZD8186 with 2 day on AZD2014 concurrent dosing schedule in 786-0 gave 41% and 22% regression respectively in HCC70. The anti-tumour effects were associated with increased depth and duration of inhibition of AKT pathway biomarkers, but significantly also modification of biomarkers associated with cellular metabolic function and survival pathways. The ability of intermittent doses of the combination regimen to deliver tumour regression establishes the principle that it is possible to move away from chronic pathway suppression, offering the flexibility to mitigate potential tolerability challenges, potential acute resistance mechanisms, but also drive increased phenotypic effects in the tumour. Citation Format: Urs Hancox, Urszula Polanska, James T. Lynch, Carol Lenaghan, Cath Trigwell, Oona Depuelch, Phillippa Dudley, Juliana Maynard, Lara Ward, Kevin Hudson, Jon Curwen, Francisco Cruzalegui, Stephen Green, Klinowska Teresa, Simon T. Barry. Combining AZD8186, an inhibitor of PI3Kbeta, with inhibitors of PI3Kalpha and mTORC1/2 gives comprehensive pathway suppression and enhanced antitumor activity in PTEN null tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2015-4696