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Precision oncology is the ultimate goal of cancer treatment, i.e., to treat cancer and only cancer, leaving all the remaining cells and tissues as intact as possible. Classical chemotherapy and radiotherapy, however, are still effective in many patients with cancer by effectively inducing apoptosis of cancer cells. Cancer cells might resist apoptosis via the anti-apoptotic effects of the inhibitor of apoptosis proteins. Recently, the inhibitors of those proteins have been developed with the goal of enhancing the cytotoxic effects of chemotherapy and radiotherapy, and one of them, xevinapant, has already demonstrated effectiveness in a phase II clinical trial. This class of drugs represents an example of synergism between classical cytotoxic chemo- and radiotherapy and new targeted therapy.

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) are among the first layer of molecules that receive, interpret, and transduce signals leading to distinct cancer cell phenotypes. Since the discovery of the tooth-lid factor-later characterized as the epidermal growth factor (EGF)-and its high-affinity binding EGF receptor, HER kinases have emerged as one of the commonly upregulated or hyperactivated or mutated kinases in epithelial tumors, thus allowing HER1-3 family members to regulate several hallmarks of cancer development and progression. Each member of the HER family exhibits shared and unique structural features to engage multiple receptor activation modes, leading to a range of overlapping and distinct phenotypes. EGFR, the founding HER family member, provided the roadmap for the development of the cell surface RTK-directed targeted cancer therapy by serving as a prototype/precursor for the currently used HER-directed cancer drugs. We herein provide a brief account of the discoveries, defining moments, and historical context of the HER family and guidepost advances in basic, translational, and clinical research that solidified a prominent position of the HER family in cancer research and treatment. We also discuss the significance of HER3 pseudokinase in cancer biology; its unique structural features that drive transregulation among HER1-3, leading to a superior proximal signaling response; and potential role of HER3 as a shared effector of acquired therapeutic resistance against diverse oncology drugs. Finally, we also narrate some of the current drawbacks of HER-directed therapies and provide insights into postulated advances in HER biology with extensive implications of these therapies in cancer research and treatment., (© 2020 Elsevier Inc. All rights reserved.)