Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

Marcus, Ruscetti, John P., Morris, Riccardo, Mezzadra, James, Russell, Josef, Leibold, Paul B, Romesser, Janelle, Simon, Amanda, Kulick, Yu-jui, Ho, Myles, Fennell, Jinyang, Li, Robert J., Norgard, John E., Wilkinson, Direna, Alonso-Curbelo, Ramya, Sridharan, Daniel A., Heller, Elisa, de Stanchina, Ben Z, Stanger, Charles J, Sherr, Scott W, Lowe

Cell |

Summary 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) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances 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 models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.