Inhibition of JAK2/STAT3 by pacritinib synergizes with chemotherapy in esophageal carcinoma

Abstract

The poor outcomes associated with esophageal carcinoma, particularly in advanced stages, necessitate the development of new treatment strategies. This study examines the efficacy of pacritinib, a multi-kinase inhibitor, both alone and in combination with carboplatin, in preclinical esophageal carcinoma models. Six esophageal carcinoma cell lines (KYSE-70, OE33, FLO-1, KYAE-1, ESO 26, and HCE-6) were treated with pacritinib, resulting in a dose-dependent reduction in cell viability. Combination index (CI) analysis demonstrated strong synergy between pacritinib and carboplatin across this panel of cell lines. In in vivo esophageal carcinoma xenograft model, pacritinib alone significantly reduced tumor growth and improved survival rates compared to control. Notably, the combination of pacritinib and carboplatin further reduced tumor growth and improved survival rates compared to either treatment alone. Toxicity assessment showed that neither single-agent nor combination treatment resulted in significantly altered levels of body weight and serum markers, supporting the safety profile of pacritinib in combination with carboplatin. Mechanistic studies revealed that while pacritinib inhibited the phosphorylation of JAK, STAT3, and IRAK1 in esophageal carcinoma cells, it is the suppression of the JAK/STAT3 pathway, rather than IRAK1, that is responsible for the synergistic effect with carboplatin. Our findings indicate that pacritinib possesses potent anti-tumor activity in esophageal carcinoma and enhances the efficacy of carboplatin through the suppression of JAK/STAT3 signaling, warranting further clinical investigation.