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
Received: 14 February 2021 / Revised: 25 February 2021 / Accepted: 26 February 2021 / Published: 2 March 2021
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.