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...
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| Veröffentlicht in: | Cancers 2023-02, Vol.15 (4), p.1130 |
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| creator | Guidi, Lorenzo Pellizzari, Gloria Tarantino, Paolo Valenza, Carmine Curigliano, Giuseppe |
| 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
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. |
| doi_str_mv | 10.3390/cancers15041130 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers15041130</identifier><identifier>PMID: 36831473</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Antibodies ; Antigens ; Antitumor agents ; Breast cancer ; Cancer therapies ; Cell cycle ; Chemotherapy ; Cytotoxicity ; DNA damage ; Drug resistance ; ErbB-2 protein ; FDA approval ; Genetic aspects ; Immune checkpoint inhibitors ; Kinases ; Medical prognosis ; Metastases ; Monoclonal antibodies ; Patients ; Protein transport ; Protein-tyrosine kinase ; Review ; Solid tumors ; Statins ; Trastuzumab</subject><ispartof>Cancers, 2023-02, Vol.15 (4), p.1130</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 by the authors. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-13e757a24165a3cf68173ffa8ad0e17553279fb944d68a4dc2c1effdc1d125373</citedby><cites>FETCH-LOGICAL-c488t-13e757a24165a3cf68173ffa8ad0e17553279fb944d68a4dc2c1effdc1d125373</cites><orcidid>0000-0001-8686-0228 ; 0000-0003-1150-0345 ; 0000-0003-1781-2518</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954056/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954056/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36831473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guidi, Lorenzo</creatorcontrib><creatorcontrib>Pellizzari, Gloria</creatorcontrib><creatorcontrib>Tarantino, Paolo</creatorcontrib><creatorcontrib>Valenza, Carmine</creatorcontrib><creatorcontrib>Curigliano, Giuseppe</creatorcontrib><title>Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><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
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.</description><subject>Antibodies</subject><subject>Antigens</subject><subject>Antitumor agents</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>DNA damage</subject><subject>Drug resistance</subject><subject>ErbB-2 protein</subject><subject>FDA approval</subject><subject>Genetic aspects</subject><subject>Immune checkpoint inhibitors</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Monoclonal antibodies</subject><subject>Patients</subject><subject>Protein transport</subject><subject>Protein-tyrosine kinase</subject><subject>Review</subject><subject>Solid tumors</subject><subject>Statins</subject><subject>Trastuzumab</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptks1rHCEYxqW0NCHNubci9NLLJH7NONNDYTPNR2FLIaRncZ3XicusbtQp5L-v23ywCdWDL_p7Hn3lQegjJSecd-TUaG8gJloTQSknb9AhI5JVTdOJt3v1ATpOaU3K4JzKRr5HB7xpORWSH6K7a0gu5Z0TzgEvfHarMNxX3-M84j749TzqDAnf6DhCdn7EV-fXDDuPzyLolHH_7xFf8c8wgZknHfFS-yEZvQVcCnwx5zkC7m_1NIEfIX1A76yeEhw_rkfo98X5TX9VLX9d_ugXy8qIts0V5SBrqZmgTa25sU1LJbdWt3ogQGVdcyY7u-qEGJpWi8EwQ8HawdCBsppLfoS-Pfhu59UGBgM-Rz2pbXQbHe9V0E69PPHuVo3hj-q6WpC6KQZfHg1iuJshZbVxycA0aQ9hTorJlhBJOWsL-vkVug5z9KW9QslO1Kzt9qhRT6Cct6Hca3amaiEFJ5RQSgp18h-qzAE2zgQP1pX9F4LTB4GJIaUI9rlHStQuKOpVUIri0_7XPPNPseB_AQNpuTk</recordid><startdate>20230210</startdate><enddate>20230210</enddate><creator>Guidi, Lorenzo</creator><creator>Pellizzari, Gloria</creator><creator>Tarantino, Paolo</creator><creator>Valenza, Carmine</creator><creator>Curigliano, Giuseppe</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8686-0228</orcidid><orcidid>https://orcid.org/0000-0003-1150-0345</orcidid><orcidid>https://orcid.org/0000-0003-1781-2518</orcidid></search><sort><creationdate>20230210</creationdate><title>Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges</title><author>Guidi, Lorenzo ; Pellizzari, Gloria ; Tarantino, Paolo ; Valenza, Carmine ; Curigliano, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c488t-13e757a24165a3cf68173ffa8ad0e17553279fb944d68a4dc2c1effdc1d125373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antibodies</topic><topic>Antigens</topic><topic>Antitumor agents</topic><topic>Breast cancer</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>DNA damage</topic><topic>Drug resistance</topic><topic>ErbB-2 protein</topic><topic>FDA approval</topic><topic>Genetic aspects</topic><topic>Immune checkpoint inhibitors</topic><topic>Kinases</topic><topic>Medical prognosis</topic><topic>Metastases</topic><topic>Monoclonal antibodies</topic><topic>Patients</topic><topic>Protein transport</topic><topic>Protein-tyrosine kinase</topic><topic>Review</topic><topic>Solid tumors</topic><topic>Statins</topic><topic>Trastuzumab</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guidi, Lorenzo</creatorcontrib><creatorcontrib>Pellizzari, Gloria</creatorcontrib><creatorcontrib>Tarantino, Paolo</creatorcontrib><creatorcontrib>Valenza, Carmine</creatorcontrib><creatorcontrib>Curigliano, Giuseppe</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guidi, Lorenzo</au><au>Pellizzari, Gloria</au><au>Tarantino, Paolo</au><au>Valenza, Carmine</au><au>Curigliano, Giuseppe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2023-02-10</date><risdate>2023</risdate><volume>15</volume><issue>4</issue><spage>1130</spage><pages>1130-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>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. 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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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36831473</pmid><doi>10.3390/cancers15041130</doi><orcidid>https://orcid.org/0000-0001-8686-0228</orcidid><orcidid>https://orcid.org/0000-0003-1150-0345</orcidid><orcidid>https://orcid.org/0000-0003-1781-2518</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Antigens Antitumor agents Breast cancer Cancer therapies Cell cycle Chemotherapy Cytotoxicity DNA damage Drug resistance ErbB-2 protein FDA approval Genetic aspects Immune checkpoint inhibitors Kinases Medical prognosis Metastases Monoclonal antibodies Patients Protein transport Protein-tyrosine kinase Review Solid tumors Statins Trastuzumab |
| title | Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges |
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