PLX253665

GSE141684: Senescence triggers vascular remodeling and new therapeutic vulnerabilities in pancreas cancer

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. A combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can potently suppress PDAC proliferation through induction of RB-mediated senescence and simultaneously trigger a senescence-associated secretory phenotype (SASP) capable of remodeling the tumor-immune microenvironment. Using immunocompetent mouse models of PDAC, we find that this senescence-inducing therapy produces a pro-angiogenic SASP leading to increased vascularization that culminates in enhanced drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation produced by the pro-senescence therapy stimulates the accumulation of CD8+ T cells into immunologically cold PDAC, 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. SOURCE: Yu-Jui Ho (hoy@mskcc.org) - Memorial Sloan Kettering Cancer Center