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
PMCID: PMC6711172
DOI/URL:
Notes: Sci. -- Cited By :1 -- Export Date: 2 January 2019 -- Article -- CODEN: SCIEA C2 - 30573629 -- Source: Scopus
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MSK Authors
  1. Matthew Bott
    135 Bott
  2. Scott W Lowe
    249 Lowe
  3. Sha Tian
    14 Tian
  4. Paul Bernard Romesser
    188 Romesser
  5. Myles Ashley Fennell
    22 Fennell
  6. Charles Rudin
    488 Rudin
  7. John Thomas Poirier
    82 Poirier
  8. Chi-Chao   Chen
    19 Chen
  9. Timour Baslan
    46 Baslan
  10. Judith Carolin Feucht
    23 Feucht
  11. Amanda Kulick
    24 Kulick
  12. Josef Leibold
    16 Leibold
  13. Yu-jui Ho
    40 Ho
  14. Hsuan An Chen
    9 Chen