Englander Institute for Precision Medicine

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

TitleMulti-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models.
Publication TypeJournal Article
Year of Publication2025
AuthorsTyrakis PA, Kampjut D, Steele GF, H Lindström JG, Chirnomas D, Hopkins BD, Goncalves MD, Mukherjee S, Cantley LC, Maddocks ODK
JournalBr J Cancer
Date Published2025 May 13
ISSN1532-1827
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.

DOI10.1038/s41416-025-03035-z
Alternate JournalBr J Cancer
PubMed ID40360883
PubMed Central ID3187555

Weill Cornell Medicine Englander Institute for Precision Medicine 413 E 69th Street
Belfer Research Building
New York, NY 10021