Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models
Abstract Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29425-y |
| _version_ | 1827984308526120960 |
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| author | María Jimena Rodriguez María Cecilia Perrone Marina Riggio Marta Palafox Valeria Salinas Andrés Elia Natali Daiana Salgueiro Andrea Eugenia Werbach María Paula Marks Marcelo A. Kauffman Luciano Vellón Violeta Serra Virginia Novaro |
| author_facet | María Jimena Rodriguez María Cecilia Perrone Marina Riggio Marta Palafox Valeria Salinas Andrés Elia Natali Daiana Salgueiro Andrea Eugenia Werbach María Paula Marks Marcelo A. Kauffman Luciano Vellón Violeta Serra Virginia Novaro |
| author_sort | María Jimena Rodriguez |
| collection | DOAJ |
| description | Abstract Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence. |
| first_indexed | 2024-04-09T22:58:33Z |
| format | Article |
| id | doaj.art-894327144ae548bf939fc2408e72085d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:58:33Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-894327144ae548bf939fc2408e72085d2023-03-22T11:08:31ZengNature PortfolioScientific Reports2045-23222023-02-0113111510.1038/s41598-023-29425-yTargeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer modelsMaría Jimena Rodriguez0María Cecilia Perrone1Marina Riggio2Marta Palafox3Valeria Salinas4Andrés Elia5Natali Daiana Salgueiro6Andrea Eugenia Werbach7María Paula Marks8Marcelo A. Kauffman9Luciano Vellón10Violeta Serra11Virginia Novaro12Instituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAVall D’Hebron Institute of Oncology (VHIO), Experimental Therapeutics GroupHospital JM Ramos Mejía, Neurogenetics Unit, C1221ADC CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAHospital JM Ramos Mejía, Neurogenetics Unit, C1221ADC CABAInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAVall D’Hebron Institute of Oncology (VHIO), Experimental Therapeutics GroupInstituto de Biología y Medicina Experimental (IBYME-CONICET), Protein Kinases and Cancer Laboratory, ADN1428 CABAAbstract Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence.https://doi.org/10.1038/s41598-023-29425-y |
| spellingShingle | María Jimena Rodriguez María Cecilia Perrone Marina Riggio Marta Palafox Valeria Salinas Andrés Elia Natali Daiana Salgueiro Andrea Eugenia Werbach María Paula Marks Marcelo A. Kauffman Luciano Vellón Violeta Serra Virginia Novaro Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models Scientific Reports |
| title | Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models |
| title_full | Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models |
| title_fullStr | Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models |
| title_full_unstemmed | Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models |
| title_short | Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models |
| title_sort | targeting mtor to overcome resistance to hormone and cdk4 6 inhibitors in er positive breast cancer models |
| url | https://doi.org/10.1038/s41598-023-29425-y |
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