Coexistent <i>PTEN</i> and <i>PIK3CA</i> alterations hyperactivate mTORC1 signaling in endometrial cancers and cause their selective sensitivity to mTORC1 inhibition
We have found the mechanistic consequences of <i>PTEN/PIK3CA</i> co-alterations in endometrial tumors and that these mutations result in a profound hyperactivation of mTORC1 signaling. Single mutant tumors are sensitive to PI3K inhibition but those with both mutations are insensitive to PI3K or AKT inhibition but are exquisitely dependent on mTORC1 kinase. This provides strong preclinical rationale for targeting mTORC1, alone or combined with RAS inhibition (in RAS co-mutant tumors), as an effective therapeutic strategy.
Authors
- Radha Mukherjee
- Justin Meyerowitz (ORCID: https://orcid.org/0000-0001-7194-8286)
- Simon T. Barry
- Sang Ah Yi (ORCID: https://orcid.org/0000-0002-7048-0252)
- Harika Gundlapalli
- Heeseon An (ORCID: https://orcid.org/0000-0002-8518-4077)
- Neal Rosen (ORCID: https://orcid.org/0000-0002-8307-654X)
- Hilla Solomon (ORCID: https://orcid.org/0000-0003-1712-3202)
- Mallika Singh
- Alison M. Schram (ORCID: https://orcid.org/0000-0002-6070-2413)
- Britta Weigelt
- Yu Chi Yang
- Michael Tribuzio
- Xiaoping Chen
- Julia Meredith
- Elisa de Stanchina
Institutions
- AstraZeneca (United Kingdom) (GB)
- Memorial Sloan Kettering Cancer Center (US)
- Revolution Medicines (United States) (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-14
- DOI
- https://doi.org/10.64898/2026.02.12.705558
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Melanoma Research Alliance
- Geoffrey Beene Cancer Research Center
- Emerson Collective
- National Institutes of Health