The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models

Citació

  • Sanz-Álvarez M, Martín-Aparicio E, Luque M, Zazo S, Martínez-Useros J, Eroles P, Rovira A, Albanell J, Madoz-Gúrpide J, Rojo F. The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models. Cancers (Basel). 2021;13(11):2778. DOI: 10.3390/cancers13112778

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Descripció

  • Resum

    The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.
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