Self-inhibition of HER2 and HER3 at fever temperatures may prevent their hetero-dimerization

Abstract

HER2 and HER3 receptors dimerize into potent pro-oncogenic complexes involved in various aggressive and recurrent tumors. The role of febrile temperatures on the formation of HER2:HER3 complexes is unknown. To this end, molecular dynamics simulations of HER2 and HER3 were performed in the 37 °C–40 °C range. HER2 and ligand-free HER32 display inactive conformers that cannot form complexes at 40 °C, while maintaining their extended conformations able to dimerize in the 37 °C–39 °C range. Thermal therapy at particular fever points may complement existing therapy options for HER2-relevant cancers.

Communicated by Ramaswamy H. Sarma

Keywords:

• HER2
• HER3
• fever
• cancer
• thermal therapy
• molecular dynamics

Acknowledgments

We thank Dr. Lei Li and Dr. Harinda Rajapaksha for technical support. Funding was provided by Chonnam National University and by National Research Foundation of Korea, grant 2021R1I1A2059587 (RCS). This work was supported by Oracle Cloud credits and related resources provided by the Oracle for Research program, grant CPQ-2615425 (RCS).

Authors’ contributions

Conceptualization, Methodology, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Funding acquisition, Supervision: RCS. Methodology, Formal analysis, Writing - Original Draft: PKS.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

Korean National Research Foundation.