Abstract
Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints.
| Original language | English |
|---|---|
| Article number | 110285 |
| Journal | Cell Reports |
| Volume | 38 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 Feb 2022 |
Bibliographical note
Funding Information:This work was funded by National Institutes of Health CA122216 (to M.M.M.) and GM109176 (to N.J.), Susan G. Komen Foundation CCR14299947 (to N.J.), and postdoctoral fellowship grants from the Susan G. Komen Foundation (to M.R.C.), the American Association for Cancer Research – Genentech BioOncology Fellowship (to M.R.C.), and the Ramon Areces Foundation (to A.R.S.). The authors would like to thank James Lee for technical assistance with cell-based studies.
Funding Information:
This work was funded by National Institutes of Health CA122216 (to M.M.M.) and GM109176 (to N.J.), Susan G. Komen Foundation CCR14299947 (to N.J.), and postdoctoral fellowship grants from the Susan G. Komen Foundation (to M.R.C.), the American Association for Cancer Research ? Genentech BioOncology Fellowship (to M.R.C.), and the Ramon Areces Foundation (to A.R.S.). The authors would like to thank James Lee for technical assistance with cell-based studies. M.M.M. and M.R.C. designed the study and wrote the manuscript. M.R.C. J.O. E.P. Y.Z. and M.S. performed most of the cell-based studies. V.S. and M.S. performed most of the mouse studies. A.R.-S. performed the CRISPR knockout. N.J. designed many of the HER3 mutations and structural modifications. All authors have read, commented on, and approved the manuscript. The authors declare no competing interests.
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