Senescence-induced vascular remodeling creates new therapeutic vulnerabilities in pancreas cancer

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB)-mediated senescence, a tumor suppressive process accompanied by a non-cell autonomous program defined as the senescence-associated secretory phenotype (SASP). In genetically and histopathologically accurate mouse models of PDAC, this senescence-inducing therapy produces a SASP that includes pro-angiogenic factors that promote tumor vascularization, culminating in enhanced drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8 + T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC, therapy- induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.