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

  • Br J Cancer. 2025 May 13. doi: 10.1038/s41416-025-03035-z.
Petros A Tyrakis  1 ,  Domen Kampjut  1 ,  Georgina F Steele  1 ,  H Jonathan G Lindström  1 ,  Deborah Chirnomas  1 ,  Benjamin D Hopkins  2 ,  Marcus D Goncalves  3 ,  Siddhartha Mukherjee  4 ,  Lewis C Cantley  5 ,  Oliver D K Maddocks  6
Affiliations
  • 1. Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
  • 2. Englander Institute for Precision Medicine, Meyer Cancer Center, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
  • 3. Department of Medicine, NYU Langone Health, New York, NY, USA.
  • 4. Department of Medicine, Columbia University Irving Cancer Research Center, Columbia University, New York, NY, 10032, USA.
  • 5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 6. Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK. [email protected].
PMID: 40360883 DOI: 10.1038/s41416-025-03035-z
Abstract

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.

Products