HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors
Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, in...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/1047 |
| _version_ | 1797416039438352384 |
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| author | Kimio Yonesaka |
| author_facet | Kimio Yonesaka |
| author_sort | Kimio Yonesaka |
| collection | DOAJ |
| description | Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including secondary EGFR-mutation and its downstream RAS/RAF mutation. Since the discovery of the role of human epidermal growth factor receptor 2 (HER2) and HER3 in drug resistance, HER2- or HER3-targeting treatment strategies using monoclonal antibodies have been intensively examined and have demonstrated impressive responsiveness and limitations. Finally, an innovative targeted therapy called antibody drug conjugates (ADC) has provided a solution to overcome this resistance. Specifically, a new cleavable linker-payload system enables stable drug delivery to cancer cells, causing selective destruction. HER2-targeting ADC trastuzumab deruxtecan demonstrated promising responsiveness in patients with HER2-positive CRC, in a phase 2 clinical trial (objective response rate = 45.3%). Furthermore, HER3-targeting patritumab deruxtecan, another ADC, exhibited impressive tumor shrinkage in pretreated patients with EGFR-mutated NSCLC, in a phase 1 clinical trial. This manuscript presents an overview of the accumulated evidence on HER2- and HER3-targeting therapy, especially ADCs, and discussion of remaining issues for further improving these treatments in cancers resistant to EGFR inhibitors. |
| first_indexed | 2024-03-09T05:58:01Z |
| format | Article |
| id | doaj.art-2a5fb476dc4c47a0ab67943c97f89da7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T05:58:01Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2a5fb476dc4c47a0ab67943c97f89da72023-12-03T12:11:32ZengMDPI AGCancers2072-66942021-03-01135104710.3390/cancers13051047HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR InhibitorsKimio Yonesaka0Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi Osaka-Sayamashi, Osaka 589-8511, JapanEpidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including secondary EGFR-mutation and its downstream RAS/RAF mutation. Since the discovery of the role of human epidermal growth factor receptor 2 (HER2) and HER3 in drug resistance, HER2- or HER3-targeting treatment strategies using monoclonal antibodies have been intensively examined and have demonstrated impressive responsiveness and limitations. Finally, an innovative targeted therapy called antibody drug conjugates (ADC) has provided a solution to overcome this resistance. Specifically, a new cleavable linker-payload system enables stable drug delivery to cancer cells, causing selective destruction. HER2-targeting ADC trastuzumab deruxtecan demonstrated promising responsiveness in patients with HER2-positive CRC, in a phase 2 clinical trial (objective response rate = 45.3%). Furthermore, HER3-targeting patritumab deruxtecan, another ADC, exhibited impressive tumor shrinkage in pretreated patients with EGFR-mutated NSCLC, in a phase 1 clinical trial. This manuscript presents an overview of the accumulated evidence on HER2- and HER3-targeting therapy, especially ADCs, and discussion of remaining issues for further improving these treatments in cancers resistant to EGFR inhibitors.https://www.mdpi.com/2072-6694/13/5/1047EGFRHER2HER3ADCtrastuzumab deruxtecan (T-DXd)patritumab deruxtecan |
| spellingShingle | Kimio Yonesaka HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors Cancers EGFR HER2 HER3 ADC trastuzumab deruxtecan (T-DXd) patritumab deruxtecan |
| title | HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors |
| title_full | HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors |
| title_fullStr | HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors |
| title_full_unstemmed | HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors |
| title_short | HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors |
| title_sort | her2 her3 targeting antibody drug conjugates for treating lung and colorectal cancers resistant to egfr inhibitors |
| topic | EGFR HER2 HER3 ADC trastuzumab deruxtecan (T-DXd) patritumab deruxtecan |
| url | https://www.mdpi.com/2072-6694/13/5/1047 |
| work_keys_str_mv | AT kimioyonesaka her2her3targetingantibodydrugconjugatesfortreatinglungandcolorectalcancersresistanttoegfrinhibitors |