ArticleMolecular oncology2022
The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings.
Article in Molecular oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- The sleeping threat: targeting cancer dormancy to transform metastasis therapy.Nature reviews. Cancer · 2026Review
- MultifunctionalRSC advances · 2025Review
- Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation.Cancer research · 2025Article
- Symmetrical di-substituted phenylamino-RSC advances · 2025Article
- Inflammation drives tumor growth in an immunocompetent implantable metastasis model.Research square · 2024Article
- Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7International journal of molecular sciences · 2024Article
- Outlook and opportunities for engineered environments of breast cancer dormancy.Science advances · 2024Review
- RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding.Journal of experimental & clinical cancer research : CR · 2024Article
- Regulation of PI3K signaling in cancer metabolism and PI3K-targeting therapy.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2024Review
- Exploring the therapeutic potential of ADC combination for triple-negative breast cancer.Cellular and molecular life sciences : CMLS · 2023Review
- Recent biological applications of heterocyclic hybrids containingRSC advances · 2023Review
- Host-Related Factors in the Interplay among Inflammation, Immunity and Dormancy in Breast Cancer Recurrence and Prognosis: An Overview for Clinicians.International journal of molecular sciences · 2023Review
- Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment.International journal of molecular sciences · 2023Review
- Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis.Frontiers in pharmacology · 2023Review
- Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s).Cancer research · 2022Review
- Review
- Acetic Acid Mediated for One-Pot Synthesis of Novel PyrazolylPharmaceutics · 2022Article
- Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-ACS omega · 2022Article
- Clinical and Biological Aspects of Disseminated Tumor Cells and Dormancy in Breast Cancer.Frontiers in cell and developmental biology · 2022Review
- Pyrazolyl-s-triazine with indole motif as a novel of epidermal growth factor receptor/cyclin-dependent kinase 2 dual inhibitors.Frontiers in chemistry · 2022Article
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Authors and funding
9 authors at 3 institutions in 1 country.
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Abstract
Dormant, disseminated tumor cells (DTCs) are thought to be the source of breast cancer metastases several years or even decades after initial treatment. To date, a selective therapy that leads to their elimination has not been discovered. While dormant DTCs resist chemotherapy, evidence suggests that this resistance is driven not by their lack of proliferation, but by their engagement of the surrounding microenvironment, via integrin-β1-mediated interactions. Because integrin-β1-targeted agents have not been translated readily to the clinic, signaling nodes downstream of integrin-β1 could serve as attractive therapeutic targets in order to sensitize dormant DTCs to therapy. By probing a number of kinases downstream of integrin-β1, we determined that PI3K inhibition with either a tool compounds or a compound (PF-05212384; aka Gedatolisib) in clinical trials robustly sensitizes quiescent breast tumor cells seeded in organotypic bone marrow cultures to chemotherapy. These results motivated the preclinical study of whether Gedatolisib-with or without genotoxic therapy-would reduce DTC burden and prevent metastases. Despite promising results in organotypic culture, Gedatolisib failed to reduce DTC burden or delay, reduce or prevent metastasis in murine models of either triple-negative or estrogen receptor-positive breast cancer dissemination and metastasis. This result held true whether analyzing Gedatolisib on its own (vs. vehicle-treated animals) or in combination with dose-dense doxorubicin and cyclophosphamide (vs. animals treated only with dose-dense chemotherapies). These data suggest that PI3K is not the node downstream of integrin-β1 that confers chemotherapeutic resistance to DTCs. More broadly, they cast doubt on the strategy to target PI3K in order to eliminate DTCs and prevent breast cancer metastasis.
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