Dual PI3K/mTOR inhibition is required to combat resistance to CDK4/6 inhibitor and endocrine therapy in PIK3CA-mutant breast cancer

  • Sci Transl Med. 2025 Dec 17;17(829):eadp5088. doi: 10.1126/scitranslmed.adp5088.
Carla L Alves  1 ,  Leena Karimi  1 ,  Mikkel G Terp  1 ,  Mie K Jakobsen  1 ,  Fiona H Zhou  2  3 ,  Benedetta Policastro  1 ,  Nikoline Nissen  1 ,  Lene E Johansen  1 ,  Tina Ravnsborg  4 ,  Leila Eshraghi  2  3 ,  Sana Tamboowala  2  3 ,  Ole N Jensen  4 ,  Elgene Lim  2  3 ,  Henrik J Ditzel  1  5  6
Affiliations
  • 1. Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark.
  • 2. Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia.
  • 3. St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
  • 4. Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
  • 5. Department of Oncology, Odense University Hospital, 5000 Odense, Denmark.
  • 6. Department of Clinical Research, University of Southern Denmark, 5250 Odense, Denmark.
PMID: 41406241 DOI: 10.1126/scitranslmed.adp5088
Abstract

Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor-positive (ER+) breast Cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K/Akt/mTOR pathway to the standard combined CDK4/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K/Akt/mTOR pathway inhibitors in breast Cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4/6i and ET and exhibiting PIK3CA, PTEN, or Akt1 mutations. PIK3CA-mutant, PTEN-wild type, CDK4/6i-resistant, and ET-resistant models required the addition of the dual PI3K/mTOR Inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1α pathway through both mTORC1 inhibition and PI3K/AKT-mediated modulation of GSK3α/β activity. Conversely, PIK3CA-wild type, PTEN-null cells benefited from triple combinations incorporating either the Akt Inhibitor capivasertib or the dual mTORC1/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of PIK3CA- or Akt1-mutant and PTEN-wild type CDK4/6i-resistant patient-derived organoids compared with the α-specific PI3K Inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER+ breast tumors harboring alterations of the PI3K/Akt/mTOR pathway including PIK3CA or Akt1 mutations.

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