Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models

Background: While PI3K/Akt/mTOR signalling plays a critical role in Cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation.

Methods: Using models of endometrial and breast Cancer, we evaluated the efficacy of a multi-node PI3K/Akt/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 Inhibitor sapanisertib, PI3Kα Inhibitor serabelisib and an insulin-supressing diet. Pathway signalling inhibition versus a range of single-node inhibitors was measured via S6, Akt and 4E-BP1 phosphorylation.

Results: The serabelisib-sapanisertib combination more effectively suppressed PI3K/Akt/mTOR pathway signalling, particularly 4E-BP1, than single-node inhibitors, including alpelisib, capivasertib, inavolisib, everolimus and mutant-specific PI3K inhibitors RLY-2608 and STX-478. Serabelisib plus sapanisertib combined effectively with a range of Other therapeutics, such as chemotherapies, hormone targeted therapies and CDK4/6 inhibitors. In xenograft models, sapanisertib, serabelisib plus paclitaxel/Insulin supressing diet achieved complete inhibition of tumour growth/tumour regression.

Conclusion: Multi-node PI3K/Akt/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast Cancer, supporting continued clinical development in these and Other solid tumours.