Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges
The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 i...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/4/1130 |
| _version_ | 1797621849125814272 |
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| author | Lorenzo Guidi Gloria Pellizzari Paolo Tarantino Carmine Valenza Giuseppe Curigliano |
| author_facet | Lorenzo Guidi Gloria Pellizzari Paolo Tarantino Carmine Valenza Giuseppe Curigliano |
| author_sort | Lorenzo Guidi |
| collection | DOAJ |
| description | The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and <i>SLX4</i> loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents. |
| first_indexed | 2024-03-11T09:02:55Z |
| format | Article |
| id | doaj.art-50b07919978145708ad595e94109c609 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:02:55Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-50b07919978145708ad595e94109c6092023-11-16T19:36:36ZengMDPI AGCancers2072-66942023-02-01154113010.3390/cancers15041130Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future ChallengesLorenzo Guidi0Gloria Pellizzari1Paolo Tarantino2Carmine Valenza3Giuseppe Curigliano4Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, ItalyThe treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and <i>SLX4</i> loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents.https://www.mdpi.com/2072-6694/15/4/1130HER2-positive breast cancerantibody-drug conjugatestrastuzumab emtansinetrastuzumab deruxtecanmechanisms of resistance |
| spellingShingle | Lorenzo Guidi Gloria Pellizzari Paolo Tarantino Carmine Valenza Giuseppe Curigliano Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges Cancers HER2-positive breast cancer antibody-drug conjugates trastuzumab emtansine trastuzumab deruxtecan mechanisms of resistance |
| title | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
| title_full | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
| title_fullStr | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
| title_full_unstemmed | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
| title_short | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
| title_sort | resistance to antibody drug conjugates targeting her2 in breast cancer molecular landscape and future challenges |
| topic | HER2-positive breast cancer antibody-drug conjugates trastuzumab emtansine trastuzumab deruxtecan mechanisms of resistance |
| url | https://www.mdpi.com/2072-6694/15/4/1130 |
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