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Molecular Cancer Research
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Cell Cycle and Senescence

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth

Xiangnan Guan, Kyle M. LaPak, Rebecca C. Hennessey, Christina Y. Yu, Reena Shakya, Jianying Zhang and Christin E. Burd
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.
2Department of Cancer Biology and 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.
3Department of Biomedical Informatics, 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.
2Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
4The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio.
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  • For correspondence: burd.25@osu.edu
DOI: 10.1158/1541-7786.MCR-16-0319 Published March 2017
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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., 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.

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.

This article is featured in Highlights of This Issue, p. 235

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received September 20, 2016.
  • Revision received December 6, 2016.
  • Accepted December 8, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Research: 15 (3)
March 2017
Volume 15, Issue 3
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Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Xiangnan Guan, Kyle M. LaPak, Rebecca C. Hennessey, Christina Y. Yu, Reena Shakya, Jianying Zhang and Christin E. Burd
Mol Cancer Res March 1 2017 (15) (3) 237-249; DOI: 10.1158/1541-7786.MCR-16-0319

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Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Xiangnan Guan, Kyle M. LaPak, Rebecca C. Hennessey, Christina Y. Yu, Reena Shakya, Jianying Zhang and Christin E. Burd
Mol Cancer Res March 1 2017 (15) (3) 237-249; DOI: 10.1158/1541-7786.MCR-16-0319
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Molecular Cancer Research
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