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- Xiangnan Guan
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- Kyle M. LaPak
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- Rebecca C. Hennessey
- 2Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
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- Christina Y. Yu
- 2Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
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- Reena Shakya
- 4The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio.
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- Jianying Zhang
- 3Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
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- Christin E. Burd
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
説明
<jats:title>Abstract</jats:title><jats:p>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., Ras mutant, Braf mutant, and Ras/Braf wild-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 vivo models.</jats:p><jats:p>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.</jats:p>
収録刊行物
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- Molecular Cancer Research
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Molecular Cancer Research 15 (3), 237-249, 2017-02-28
American Association for Cancer Research (AACR)