Inhibition of the SRC-kinase HCK restricts pancreatic cancer development and metastasis

Pancreatic cancer is an aggressive disease with a low 5-year survival rate and poor response to therapy. Here, we demonstrate that inhibition of the myeloid-specific SRC family-kinase HCK impairs pancreatic tumor growth and metastasis by enhancing the infiltration of cytotoxic effector cells, stimulating the activation of myeloid cells, and by reducing the desmoplastic microenvironment. Genetic ablation of HCK also maximizes the therapeutic efficacy of chemotherapy and immunotherapy, and improves progression-free survival in mice. Collectively, our results demonstrate that targeting HCK can overcome barriers that limit responses to therapy, and provide a compelling rationale for HCK to be considered as a drug target to improve the responsiveness of pancreatic tumors to chemotherapy and/or immune checkpoint blockade. Overall design: We performed bulk RNA sequencing on PDAC liver tumors of wild-type (WT) and HCK knock-out mice (n=5 mice per group) 3 weeks following intraplenic injection of KPC pancreatic cancer cells.