LAUSR

The trans- and juxtamembrane domains (TMD/JMD) of human epidermal growth factor receptors (HER/EGFR/ErbB) regulate the helix-helix dimerization interface to control receptor tyrosine kinase (RTK) activation. Patient-identified non-small cell lung cancer (NSCLC) mutations occur all along the EGFR (HER1) and HER2 TMD and JMD, but our structural understanding of how these patient-derived TMD/JMD mutations hijack wild-type RTK function to drive cancer is lacking. In this work, we integrate tools in experimental biophysics and computational modeling to evaluate the structural mechanism(s) driving these interactions in atomic detail. We use nuclear magnetic resonance (NMR) spectroscopy to assess how oncogenic mutations within the TMD/JMD perturb the architecture/interactions of the dimer interface. NMR-derived models are used to seed molecular dynamics (MD) simulations to probe how mutations affect TMD association and activation/stabilization via dimerization in a realistic membrane environment. We apply this strategy and focus our initial efforts on the EGFRA647T variant. We computed the free energy landscape from our simulations and show that the active state for the EGFRA647T-HER2WT heterodimer is stabilized by 10 kcal/mol. Conversely, the wild-type EGFR-HER2 heterodimer is stabilized by 5 kcal/mol for the inactive state suggesting the propensity of the EGFRA647T mutant favors the active state. These results are part of a multidisciplinary collaboration that share the common goal of constructing holistic models that detail how TMD/JMD variants are aberrantly activated in cancer. Citation Format: Christina Mercado, Abdullah Al Mamun, Younghee Park, Christine M. Lovly, Jens Meiler, Kaitlyn Ledwitch. Integrative structural models of oncogenic mutants within the trans- and juxta-membrane region of human epidermal growth factor receptors (HERs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3173.