pyrimidinones and ribociclib

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.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cellular Senescence; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cytostatic Agents; Cytotoxicity, Immunologic; Humans; Immunologic Surveillance; Intercellular Adhesion Molecule-1; Killer Cells, Natural; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Purines; Pyridines; Pyridones; Pyrimidinones; Retinoblastoma Protein; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays