Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

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 senescenceassociated 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.

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

“…In the context of cancer, senescence is often viewed as a double-edged sword, on one hand driving tumor stasis, but on the other providing a means of therapy resistance, and fostering a microenvironment favoring inflammation, invasion, and angiogenesis (44)(45)(46)(47)(48). Further understanding the role of glycogen in cancer senescence may provide a window into modulating this fine balance (49,50).…”

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

“…Recently, there has been rising interest in targeting MEK and CDK4/6 for PDAC treatment as mutant KRas promotes MEK activation and CDKN2A loss causes CDK4/6 activation. Results from preclinical models have been promising [182].…”

“…Interestingly, the efficacy of that combination was greatly enhanced in immunocompetent mice since it induced a senescence-associated secretory phenotype (SASP) that promoted natural killer cell recruitment and cytotoxicity in the tumors. In pancreatic ductal adenocarcinoma, the same MEK-CDK4 inhibitor combination triggered SASP-dependent tumor vascularization that facilitated chemotherapy uptake as well as increased CD8+ T cell infiltration into tumors that potentiated PD-1 checkpoint blockade [182].…”

Tumor‐Activated Size‐Enlargeable Bioinspired Lipoproteins Access Cancer Cells in Tumor to Elicit Anti‐Tumor Immune Responses

“…The infiltration of CD8 + T cells in tumor account for an essential prerequisite to exert the antitumor immunotherapy. [ 4,20,21 ] We then examined the intratumoral infiltration of CD3 + CD4 − CD8 + T cells and interferon γ (IFN‐γ)‐positive CD3 + CD8 + IFN‐γ + T cells with flow cytometer examinations (Figure 5D–E; Figure S11–S12, Supporting information). TA‐OBL treatment produced the highest efficacy in increasing the infiltration of CD3 + CD4 − CD8 + T cells and cytotoxic CD3 + CD8 + IFN‐γ + T cells in tumor tissues.…”