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Mol Cancer Res. 2019 Sep;17(9):1931-1944. doi: 10.1158/1541-7786.MCR-18-0923. Epub 2019 Jun 3.

Novel Oral mTORC1/2 Inhibitor TAK-228 Has Synergistic Antitumor Effects When Combined with Paclitaxel or PI3Kα Inhibitor TAK-117 in Preclinical Bladder Cancer Models.

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Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
Pathology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
Medical School, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.
Pathology Department, IIS-Fundación Jimenez Diaz, Madrid, Spain.
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
Dana-Farber/HCC, Harvard Medical School, Boston, Massachusetts.


Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911). IMPLICATIONS: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.

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