Noncognate HER2 sensitivity to cognate EGFR allosteric inhibitors at molecular level: New uses for old drugs in gynecological tumors

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AbstractHuman epidermal growth factor receptor (EGFR) of the ErbB family kinases is a well‐established therapeutic target for malignant lung cancer, which, however, has been observed to cause the dramatic drug resistance to almost all first‐ to third‐generation ATP‐competitive inhibitors with the T790M/C797S double‐mutation at the peripheral region of its kinase active site. In recent years, allosteric inhibition of the EGFR kinase domain has evolved rapidly to overcome these clinically significant drug‐resistant mutations, leading to the discovery of a number of EGFR allosteric inhibitors. In the present study, we attempted to systematically evaluate the molecular sensitivity of existing cognate EGFR allosteric inhibitors to their noncognate HER2 target –– another druggable ErbB member that is a potential therapeutic target of diverse gynecological tumors such as breast, cervical and ovarian cancers, and shares high conservation with EGFR but still has no cognate allosteric inhibitors specifically developed for it. An integrative strategy that combined molecular modeling and biochemical inhibition assay was described to investigate the structural basis, energetics property, and dynamics behavior involved in the intermolecular interaction between the HER2 kinase domain and nine reported EGFR allosteric inhibitors at a molecular level. The inhibitor response to HER2 T798M/C805S double‐mutation was also examined and compared with their response to counterpart EGFR T790M/C797S double‐mutation. It is revealed that the EGFR allosteric inhibitors can also effectively target HER2 kinase with a similar or moderately decreased potency; they exhibit a consistent response profile to EGFR and HER2 counterpart mutations. In addition, the HER2 T798M mutation was found to considerably sensitize allosteric inhibitors EAI045 and JBJ‐04‐125‐02 by creating additional noncovalent interactions between them, while the HER2 C805S mutation was observed to have no essential effect on most allosteric inhibitors due to its spatial separation from the kinase allosteric site.