NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination Journal Article


Authors: Ruscetti, M.; Leibold, J.; Bott, M. J.; Fennell, M.; Kulick, A.; Salgado, N. R.; Chen, C. C.; Ho, Y. J.; Sanchez-Rivera, F. J.; Feucht, J.; Baslan, T.; Tian, S.; Chen, H. A.; Romesser, P. B.; Poirier, J. T.; Rudin, C. M.; de Stanchina, E.; Manchado, E.; Sherr, C. J.; Lowe, S. W.
Article Title: NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination
Abstract: Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor–a and intercellular adhesion molecule–1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non–cell autonomous mechanisms involving NK cell surveillance. © 2018 American Association for the Advancement of Science.All rights reserved.
Keywords: phenotype; protein; enzyme activity; inhibitor; molecular analysis; senescence; tumor; toxicity; enzyme; drug; cell component; cancer
Journal Title: Science
Volume: 362
Issue: 6421
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2018-12-21
Start Page: 1416
End Page: 1422
Language: English
DOI: 10.1126/science.aas9090
PROVIDER: scopus
PUBMED: 30573629
DOI/URL:
Notes: Sci. -- Cited By :1 -- Export Date: 2 January 2019 -- Article -- CODEN: SCIEA C2 - 30573629 -- Source: Scopus
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