The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models
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...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2778 |
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| author | Marta Sanz-Álvarez Ester Martín-Aparicio Melani Luque Sandra Zazo Javier Martínez-Useros Pilar Eroles Ana Rovira Joan Albanell Juan Madoz-Gúrpide Federico Rojo |
| author_facet | Marta Sanz-Álvarez Ester Martín-Aparicio Melani Luque Sandra Zazo Javier Martínez-Useros Pilar Eroles Ana Rovira Joan Albanell Juan Madoz-Gúrpide Federico Rojo |
| author_sort | Marta Sanz-Álvarez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T10:45:07Z |
| format | Article |
| id | doaj.art-a4f19bf74b984d4daa8da25ded427d74 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:45:07Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a4f19bf74b984d4daa8da25ded427d742023-11-21T22:38:47ZengMDPI AGCancers2072-66942021-06-011311277810.3390/cancers13112778The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer ModelsMarta Sanz-Álvarez0Ester Martín-Aparicio1Melani Luque2Sandra Zazo3Javier Martínez-Useros4Pilar Eroles5Ana Rovira6Joan Albanell7Juan Madoz-Gúrpide8Federico Rojo9Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainDepartment of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainDepartment of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainDepartment of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainTranslational Oncology Division, OncoHealth Institute, Health Research Institute-Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, SpainInstitute of Health Research INCLIVA-CIBERONC, 46010 Valencia, SpainCancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, SpainCancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, SpainDepartment of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainDepartment of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, SpainThe 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.https://www.mdpi.com/2072-6694/13/11/2778breast cancerresistanceanti-receptor therapytrastuzumabPI3KmTOR |
| spellingShingle | Marta Sanz-Álvarez Ester Martín-Aparicio Melani Luque Sandra Zazo Javier Martínez-Useros Pilar Eroles Ana Rovira Joan Albanell Juan Madoz-Gúrpide Federico Rojo The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models Cancers breast cancer resistance anti-receptor therapy trastuzumab PI3K mTOR |
| title | The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models |
| title_full | The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models |
| title_fullStr | The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models |
| title_full_unstemmed | The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models |
| title_short | The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models |
| title_sort | novel oral mtorc1 2 inhibitor tak 228 reverses trastuzumab resistance in her2 positive breast cancer models |
| topic | breast cancer resistance anti-receptor therapy trastuzumab PI3K mTOR |
| url | https://www.mdpi.com/2072-6694/13/11/2778 |
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