Chemical Biology Of HER2 Signaling in HER2-Mutant Non-Small Cell Lung Cancer: Molecular Mechanisms and Therapeutic Potential of Zongertinib

Human epidermal growth factor receptor 2 (HER2/ERBB2) is emerging as an oncogenic driver. HER2 alterations include gene mutations, gene amplification, and protein overexpression in cancer cells. These alterations contribute to tumorigenesis and may differentially affect patients' responses to targeted therapies. The development of molecular diagnostics, especially through NGS, is aiding the identification of HER2-driven tumors and the use of precision medicine approaches. Opportunities for the development of HER2-directed therapies have increased over recent years, with continued development of TKIs such as poziotinib, pyrotinib, and zongertinib, especially in patients with exon-20 insertion mutations. In addition, improvements in the performance of patients treated with antibody-drug conjugates (ADCs), most notably trastuzumab deruxtecan (T-DXd), have changed the course of treatment by delivering durable responses and improving survival in heavily pretreated patients. The development of targeted therapies has demonstrated that some agents exhibit activity against specific molecular targets. Their efficacy is often associated with the ability to overcome resistance mechanisms (e.g., secondary mutations, bypass mechanisms of activation, phenotypic changes), mitigate toxicities to patients, and identify suitable patients. Although newer therapeutic agents have been developed, their limitations have not been completely overcome. Combination therapies may help address some of these challenges; new inhibitors and methods to coordinate diagnostic testing with new therapies are being researched to address these obstacles. Research efforts to improve patient care and maximize treatment results will require the coordination of new therapies and molecular diagnostics to provide the best possible care for patients being treated for cancer.