Irreversible Multitargeted ErbB Family Inhibitors for Therapy of Lung and Breast Cancer
Aiwu R. He,
Marion L. Hartley,
John L. Marshall.
Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase
members (ErbB1/epidermal growth factor receptor [EGFR]/HER1, ErbB2/HER2, ErbB3/HER3, and
ErbB4/HER4), can drive the development and progression of a wide variety of malignancies, including
colorectal, head and neck, and certain non–small cell lung cancers (NSCLCs). As a result, agents that target a
specific member of the ErbB family have been developed for the treatment of cancer. These agents include
the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies
cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that
targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their
targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical
studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have
shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR
mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical
development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib
is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential
approval of these agents in a variety of solid tumor malignancies.
Keywords: Afatinib, dacomitinib, epidermal growth factor receptor, human epidermal growth factor receptor 2, neratinib, non–
small cell lung cancer, tyrosine kinase inhibitor.
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