title: Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth.
abstract: Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e.,Rasmutant,Brafmutant, andRas/Brafwild-type). When cultured in the presence of CDK4/6i-induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However,in vivo, PD-0332991-treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1-positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the antitumor immune response and promote melanoma growth in immunocompetent,in vivomodels.Implications:The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types.Mol Cancer Res; 15(3); 237-49. ©2016 AACR.
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.|Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: LaPak
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Hennessey
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Yu
authors.affiliation: The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio. burd.25@osu.edu.|Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.|The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio.
authors.forename: Christin E
authors.initials: CE
authors.lastname: Burd
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib