Functional in vivo characterisation of the role of epigenetic regulators for pancreatic cancer development and maintenance
Final Report Abstract
Accumulating evidence suggests that molecularly targeted therapies, which were originally developed to target the underlying cell autonomous genetic drivers of tumorigenesis, can provoke tumor specific immune responses. Using immunocompetent mouse models of KRAS-mutant lung adenocarcinoma, we show that a combination of MEK and CDK4/6 inhibitors can induce natural killer (NK) cell immune surveillance that is necessary for its full anti-tumor effect. Mechanistically, the drug combination - but neither agent alone - drives induction of RB-mediated cellular senescence, leading to potent cell cycle arrest and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). This, in turn, triggers cell surface expression of the adhesion molecule ICAM-1 and secretion of TNF-a, provoking NK cell-mediated targeting of senescent tumor cells and culminating in tumor regressions and longterm survival in genetically engineered mouse models of lung cancer. These studies identify a means and method of invoking a unique form of NK cell mediated immune surveillance in lung tumors through molecularly targeted therapies that induce senescence.
Publications
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Quantitative self-assembly prediction yields targeted nanomedicines. Nat Mater. 2018 Apr;17(4):361-368
Shamay Y, Shah J, Işık M, Mizrachi A, Leibold J, Tschaharganeh DF, Roxbury D, Budhathoki-Uprety J, Nawaly K, Sugarman JL, Baut E, Neiman MR, Dacek M, Ganesh KS, Johnson DC, Sridharan R, Chu KL, Rajasekhar VK, Lowe SW, Chodera JD, Heller DA
