Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by a hypovascular, immunosuppressive tumour microenvironment and is often refractory to chemotherapies and immunotherapies. Now, a new study shows that senescence induction in mouse models of Kras-mutant PDAC sensitizes tumours to such therapies.
In the study, in two mouse models of PDAC, 2-week treatment with trametinib and palbociclib (T/P) — which inhibit MEK and CDK4/6, respectively — led to induction of senescence-associated β-galactosidase activity in tumours and to decreased proliferation but not tumour regression. Intriguingly, T/P-treated tumours had improved vascularization.
Next, mouse and human PDAC cell lines as well as in vivo mouse models were used to show that the vascular remodelling is driven by senescence-associated secretory phenotype factors. These factors, which included vascular endothelial growth factor and various inflammatory molecules, altered endothelial cell proliferation and endothelial activation, respectively. “The impact of senescence on the PDAC vasculature was completely unexpected,” says Scott Lowe, corresponding author of the study.
Finally, the researchers investigated the effects of senescence induction on the efficacy of chemotherapies and immunotherapies in mouse models of PDAC. Gemcitabine (standard-of-care chemotherapy) combined with T/P increased treatment delivery to the tumour and led to large tumour regressions and significantly enhanced survival compared with mice treated with either T/P or gemcitabine alone. In addition, T/P-treated tumours had a substantial influx of PD1-expressing CD8+ T cells into the tumour microenvironment. Mice treated with T/P and anti-PD1 therapy had tumour regressions and a greater than fivefold increase in survival compared with mice treated with PD1 alone.
“Our findings suggest that senescence-induced vascular remodelling could be a powerful way to potentiate both chemotherapy and immunotherapy in solid tumours that have a dysfunctional blood vessel network, such as pancreatic cancer,” notes Lowe. “We are currently in the process of establishing a clinical trial to test the combination of MAPK and CDK4/6 inhibitors with PD1 blockade in patients with pancreatic cancer.”
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Original article
Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441.e21 (2020)
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Hindson, J. Inducing senescence sensitizes pancreatic tumours to therapies. Nat Rev Gastroenterol Hepatol 17, 316 (2020). https://doi.org/10.1038/s41575-020-0305-9
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DOI: https://doi.org/10.1038/s41575-020-0305-9