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-α 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.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / pharmacology
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Aminopyridines / therapeutic use
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Cellular Senescence
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
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Cytostatic Agents / pharmacology
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Cytostatic Agents / therapeutic use*
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Cytotoxicity, Immunologic*
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Humans
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Immunologic Surveillance*
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Intercellular Adhesion Molecule-1 / metabolism
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Killer Cells, Natural / immunology*
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases
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Molecular Targeted Therapy
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Mutation
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Proto-Oncogene Proteins p21(ras) / genetics
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Purines / pharmacology
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Purines / therapeutic use
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Pyridones / pharmacology
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Pyridones / therapeutic use
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Pyrimidinones / pharmacology
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Pyrimidinones / therapeutic use
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Retinoblastoma Protein / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Xenograft Model Antitumor Assays
Substances
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Aminopyridines
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Benzimidazoles
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Cytostatic Agents
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KRAS protein, human
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Piperazines
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Purines
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Pyridines
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Pyridones
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Pyrimidinones
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Retinoblastoma Protein
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Tumor Necrosis Factor-alpha
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Intercellular Adhesion Molecule-1
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trametinib
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abemaciclib
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Mitogen-Activated Protein Kinases
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Proto-Oncogene Proteins p21(ras)
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palbociclib
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ribociclib