Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells
To explore if the tumor microenvironment contributes to the primary resistance of HER2-positive breast cancer cells to T-DM1, we examined whether Matrigel, a basement membrane matrix that provides a three-dimensional (3D) cell culture condition, caused the primary resistance of HER2-positive, T-DM1-...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/10/2331 |
| _version_ | 1797534388037091328 |
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| author | Yukinori Endo Wen Jin Wu |
| author_facet | Yukinori Endo Wen Jin Wu |
| author_sort | Yukinori Endo |
| collection | DOAJ |
| description | To explore if the tumor microenvironment contributes to the primary resistance of HER2-positive breast cancer cells to T-DM1, we examined whether Matrigel, a basement membrane matrix that provides a three-dimensional (3D) cell culture condition, caused the primary resistance of HER2-positive, T-DM1-sensitive breast cancer cells (JIMT1 and SKBR-3 cells) to T-DM1. This is different from the conventional approach such that the cells are exposed with escalated doses of drug to establish a drug-resistant cell line. We found that these cells were able to grow and form spheroids on the Matrigel in the presence of T-DM1. We further explored the molecular mechanisms that enables these cells to be primarily resistant to T-DM1 and found that EGFR was activated in the spheroids, leading to an increased HER2 tyrosine phosphorylation. This in turn enhances cell growth signaling downstream of EGFR/HER2 in the spheroids. HER2 tyrosine phosphorylation promotes receptor internalization and degradation in the spheroids, which limits T-DM1 access to HER2 on the cell surface of spheroids. Blocking EGFR activity by erlotinib reduces HER2 tyrosine phosphorylation and enhances HER2 cell surface expression. This enables T-DM1 to gain access to HER2 on the cell surface, resumes cell sensitivity to T-DM1, and exhibits synergistic activity with T-DM1 to inhibit the formation of spheroids on Matrigel. The discovery described in this manuscript reveals a novel approach to investigate the primary resistance of HER2-positive breast cancer cells and provides an opportunity to develop a therapeutic strategy to overcome primary resistance to T-DM1 by combing T-DM1 therapy with kinase inhibitors of EGFR. |
| first_indexed | 2024-03-10T11:28:55Z |
| format | Article |
| id | doaj.art-8cd3fa4677d14cb99789779aea496858 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:28:55Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8cd3fa4677d14cb99789779aea4968582023-11-21T19:24:40ZengMDPI AGCancers2072-66942021-05-011310233110.3390/cancers13102331Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer CellsYukinori Endo0Wen Jin Wu1Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, USADivision of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, USATo explore if the tumor microenvironment contributes to the primary resistance of HER2-positive breast cancer cells to T-DM1, we examined whether Matrigel, a basement membrane matrix that provides a three-dimensional (3D) cell culture condition, caused the primary resistance of HER2-positive, T-DM1-sensitive breast cancer cells (JIMT1 and SKBR-3 cells) to T-DM1. This is different from the conventional approach such that the cells are exposed with escalated doses of drug to establish a drug-resistant cell line. We found that these cells were able to grow and form spheroids on the Matrigel in the presence of T-DM1. We further explored the molecular mechanisms that enables these cells to be primarily resistant to T-DM1 and found that EGFR was activated in the spheroids, leading to an increased HER2 tyrosine phosphorylation. This in turn enhances cell growth signaling downstream of EGFR/HER2 in the spheroids. HER2 tyrosine phosphorylation promotes receptor internalization and degradation in the spheroids, which limits T-DM1 access to HER2 on the cell surface of spheroids. Blocking EGFR activity by erlotinib reduces HER2 tyrosine phosphorylation and enhances HER2 cell surface expression. This enables T-DM1 to gain access to HER2 on the cell surface, resumes cell sensitivity to T-DM1, and exhibits synergistic activity with T-DM1 to inhibit the formation of spheroids on Matrigel. The discovery described in this manuscript reveals a novel approach to investigate the primary resistance of HER2-positive breast cancer cells and provides an opportunity to develop a therapeutic strategy to overcome primary resistance to T-DM1 by combing T-DM1 therapy with kinase inhibitors of EGFR.https://www.mdpi.com/2072-6694/13/10/2331HER2breast cancertumor microenvironmentEGFRantibody-drug conjugate (ADC)T-DM1 |
| spellingShingle | Yukinori Endo Wen Jin Wu Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells Cancers HER2 breast cancer tumor microenvironment EGFR antibody-drug conjugate (ADC) T-DM1 |
| title | Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells |
| title_full | Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells |
| title_fullStr | Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells |
| title_full_unstemmed | Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells |
| title_short | Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells |
| title_sort | tumor extrinsic factors mediate primary t dm1 resistance in her2 positive breast cancer cells |
| topic | HER2 breast cancer tumor microenvironment EGFR antibody-drug conjugate (ADC) T-DM1 |
| url | https://www.mdpi.com/2072-6694/13/10/2331 |
| work_keys_str_mv | AT yukinoriendo tumorextrinsicfactorsmediateprimarytdm1resistanceinher2positivebreastcancercells AT wenjinwu tumorextrinsicfactorsmediateprimarytdm1resistanceinher2positivebreastcancercells |