Trastuzumab-TKI combination in HER2-Positive tumors: a FAERS-Based safety profile and multimodal analysis of Tanespimycin's role in enhancing targeting of the HSP90AA1-PI3K-Akt-mTOR axis.

BACKGROUND: This study addresses the safety profiles and molecular mechanisms of trastuzumab monotherapy and its combination with lapatinib, neratinib, and tucatinib for treating HER2-positive tumors. METHODS: The research integrates a multi-platform approach, including data from the US Food and Drug Administration Adverse Event Reporting System (FAERS), network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experiments. Specifically, 38,300 FAERS reports were screened, alongside a series of in silico modeling and laboratory assays to systematically evaluate drug safety and therapeutic mechanisms. RESULTS: Pharmacovigilance analysis revealed that trastuzumab monotherapy was associated with an elevated incidence of cardiac and tumor progression-related adverse events (AEs). Combination therapies showed longer adverse event latency periods. Network pharmacology identified HSP90AA1 as a pivotal therapeutic target, while molecular docking and 100-ns molecular dynamics simulations confirmed the stable binding of each drug to HSP90AA1. In vitro assays demonstrated that HSP90AA1 is significantly overexpressed in breast cancer, driving cell proliferation and invasion, and correlates with a poor prognosis. Furthermore, the triple regimen of trastuzumab, lapatinib, and tanespimycin significantly inhibited the PI3K/Akt/mTOR signaling pathway. CONCLUSION: This study establishes a novel framework for drug safety evaluation and provides a theoretical rationale for optimizing therapeutic strategies in HER2-positive tumors. These findings highlight the potential advantages of combination therapies regarding AE latency and elucidate the critical role of HSP90AA1.