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HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi Osaka-Sayamashi, Osaka 589-8511, Japan
Academic Editor: Noriaki Sunaga
Cancers 2021, 13(5), 1047; https://doi.org/10.3390/cancers13051047
Received: 14 February 2021 / Revised: 25 February 2021 / Accepted: 26 February 2021 / Published: 2 March 2021
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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. Since the discovery of aberrantly activated human epidermal growth factor receptor-2 (HER2) and HER3 mediating resistance to EGFR-inhibitors, intensive investigations on HER2- and HER3-targeting treatments have revealed their advantages and limitations. An innovative antibody-drug conjugate (ADC) technology, with a new linker-payload system, has provided a solution to overcome this resistance. HER2-targeting ADC trastuzumab deruxtecan or HER3-targeting ADC patritumab deruxtecan, using the same cleavable linker-payload system, demonstrated promising responsiveness in patients with HER2-positive CRC or EGFR-mutated NSCLC, respectively. The current manuscript presents an overview of the accumulated evidence on HER2- and HER3-targeting therapy and discussion on remaining issues for further improvement of treatments for 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, 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. View Full-Text
Keywords: EGFR; HER2; HER3; ADC; trastuzumab deruxtecan (T-DXd); patritumab deruxtecan; NSCLC; CRC; HNSCC; EGFR-TKI EGFR; HER2; HER3; ADC; trastuzumab deruxtecan (T-DXd); patritumab deruxtecan; NSCLC; CRC; HNSCC; EGFR-TKI
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MDPI and ACS Style

Yonesaka, K. HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors. Cancers 2021, 13, 1047. https://doi.org/10.3390/cancers13051047

AMA Style

Yonesaka K. HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors. Cancers. 2021; 13(5):1047. https://doi.org/10.3390/cancers13051047

Chicago/Turabian Style

Yonesaka, Kimio. 2021. "HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors" Cancers 13, no. 5: 1047. https://doi.org/10.3390/cancers13051047

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