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Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer
Marcus Ruscetti1, John P Morris1, Riccardo Mezzadra1
1Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
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.
Insights
Combining MEK and CDK4/6 inhibitors induces senescence in KRAS-mutant pancreatic cancer. This therapy enhances chemotherapy and immunotherapy by promoting tumor vascularization and immune cell infiltration.
Area of Science:
- Oncology
- Cancer Biology
- Immunotherapy
Background:
- KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma, leading to hypovascularity, immune suppression, and resistance to standard treatments.
- Targeting KRAS-driven signaling is crucial for overcoming therapeutic resistance in PDAC.
Purpose of the Study:
- To investigate the efficacy of combining MEK and CDK4/6 inhibitors in KRAS-mutant PDAC.
- To explore the role of therapy-induced senescence and its associated secretory phenotype (SASP) in modulating the tumor microenvironment and enhancing treatment responses.
Main Methods:
- Utilized preclinical mouse models of KRAS-mutant PDAC.
- Administered a combination therapy targeting MEK and CDK4/6 to induce senescence.
- Analyzed the effects of therapy-induced senescence and SASP on tumor vascularization, immune cell infiltration, and response to chemotherapy (gemcitabine) and immunotherapy (PD-1 blockade).
Main Results:
- The combined MEK and CDK4/6 inhibition induced retinoblastoma (RB) protein-mediated senescence in PDAC cells.
- Therapy-induced senescence generated a SASP that promoted tumor vascularization, improving gemcitabine delivery and efficacy.
- SASP-mediated endothelial activation led to increased CD8+ T cell infiltration, sensitizing tumors to PD-1 checkpoint blockade.
Conclusions:
- Therapy-induced senescence, via SASP, can overcome hypovascularity and immune exclusion in KRAS-mutant PDAC.
- This approach establishes emergent susceptibilities to chemotherapy and immunotherapy in PDAC models.
- Targeting senescence offers a promising strategy to enhance the effectiveness of existing treatments for pancreatic cancer.
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