Triflupromazine and tranylcypromine alleviate primary cisplatin resistance in lung adenocarcinoma by promoting LDHA-mediated AMBRA1 ubiquitination

Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung Cancer (NSCLC), poses significant therapeutic challenges due to its aggressive nature and limited treatment options. Cisplatin is a commonly used chemotherapeutic agent for advanced LUAD, often encounters PDR, leading to rapid disease progression and tumor recurrence. In this study, we demonstrate that LDHA expression is elevated in cisplatin-resistant LUAD cell lines and correlates with poor patient prognosis. Notably, inhibiting the expression of LDHA significantly enhances cisplatin sensitivity. Mechanistically, LDHA functions through non-metabolic enzymatic activity to promote the ubiquitination and degradation of AMBRA1 by facilitating its interaction with RNF2, thereby activating Cyclin D1 and BCL2, which drives cisplatin resistance. Importantly, we identified two LDHA inhibitors, triflupromazine (TRI) and tranylcypromine (TRA), that significantly improve cisplatin efficacy both in vitro and in vivo. These findings highlight a critical role of LDHA in promoting cisplatin resistance, and suggest that targeting LDHA may represent a promising therapeutic strategy for patients with advanced LUAD.

AMBRA1; Drug resistance; LDHA; Lung adenocarcinoma; Tranylcypromine; Triflupromazine.