Lomerizine Suppresses JAK2/STAT3 Pathway Activation via CACNA1B in HNSCC

The JAK2/STAT3 pathway contributes to head and neck squamous cell carcinoma (HNSCC) progression. Using a STAT3 reporter assay, we screened a panel of 79 compounds and identified lomerizine, a calcium channel blocker approved in Japan for migraine prophylaxis, as an inhibitor of reporter activity. Lomerizine reduced JAK2 and STAT3 phosphorylation in CAL-27 cells and suppressed proliferation in the HNSCC cell models tested. Ferroptosis-associated readouts and EMT-marker changes were observed in CAL-27 HNSCC cells. In cisplatin-resistant CAL-27-DDP cells, combined lomerizine and cisplatin treatment reduced cell viability compared with cisplatin alone. Target prediction, molecular docking, cellular thermal shift assay (CETSA), and CACNA1B knockdown results implicate CACNA1B as a candidate mediator of lomerizine-associated JAK2/STAT3 changes. Lomerizine treatment also reduced tumor growth in PDX and CAL-27 xenograft models. These findings support further preclinical evaluation of lomerizine in HNSCC.