Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, exhibits anti-tumor activity and synergizes with gemcitabine in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases with few treatment options. The aberrant activation of SRC PDAC suggests it as a promising therapeutic target. Here, we evaluated the antitumor activity of olverembatinib, a novel multi-target tyrosine kinase inhibitor, as a single agent and in combination with gemcitabine, the standard chemotherapeutic backbone for PDAC treatment. Our results demonstrated that olverembatinib showed a potent anti-tumor effect and significantly enhanced the sensitivity of PDAC to gemcitabine both in vitro and in vivo. Mechanistically, olverembatinib inhibited the SRC/AKT/cMYC signaling pathway, leading to cell cycle arrest, suppression of metastasis, and induction of apoptosis. For combination with gemcitabine, the JAK1-STAT1 might serve as an important mechanistic basis of synergy. Clinically, olverembatinib exhibited promising efficacy in patients with advanced PDAC who had failed multiple prior lines of therapies, including gemcitabine-based treatment. These findings suggest that olverembatinib, either as monotherapy or in combination with gemcitabine, represents a promising novel therapeutic strategy for the treatment of PDAC.