Friends with Benefits: Microenvironmental NRG1β and HGF Mediate HER2-Targeted Resistance in L-HER2+ and HER2E Breast Cancer  Sarah B. Crist, Cyrus M. Ghajar  Cell Systems  Volume 6, Issue 3, Pages 268-270 (March 2018) DOI: 10.1016/j.cels.2018.03.005 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 L-HER2+ and HER2E Breast Cancer Cell Lines Differ in Their Resistance Mechanisms to HER2 Inhibition Both L-HER2+ (A) and HER2E (B) subsets of HER2++ breast cancer demonstrate resistance to HER2-targeted tyrosine kinase inhibitors (TKIs) lapatinib and neratinib. Watson et al. (2018) determine that the mechanism behind HER2-targeted TKI resistance is (1) mediated by the microenvironment and (2) distinct between the L-HER2+ and HER2E subsets. HER2/HER3 dimerization (C) occurs on the surface of L-HER2+ breast cancer lines in neuregulin-1β (NRG1β)-rich microenvironments. This structure alters the conformation of the ATP binding pocket on the HER2 cytoplasmic kinase domain, to which lapatinib can no longer readily bind. HER2/HER3 dimerization induces PI3K signaling to stimulate proliferation. Pertuzumab (D) inhibits cis-phosphorylation of HER3 via separation of the cytoplasmic kinase domains. This structure returns the HER2 kinase domain conformation to one that lapatinib can bind. Watson et al. (2018) propose that the combination of pertuzumab and lapatinib overcomes cis and trans phosphorylation of HER3 and HER2, respectively, to mediate effective growth inhibition. On the other hand, the HER2E subset (B) of breast cancer lines is resistant to neratinib inhibition in hepatocyte growth factor (HGF)-rich microenvironments (E). HGF binds its receptor MET to promote downstream proliferation signaling via the MAPK pathway. HGF-induced neratinib resistance of HER2E cells is reversed with a combinatorial approach employing neratinib and crizotinib, the MET-targeted TKI (F). Cell Systems 2018 6, 268-270DOI: (10.1016/j.cels.2018.03.005) Copyright © 2018 Elsevier Inc. Terms and Conditions