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Pan-Cancer Analysis Reveals Synergistic Effects of CDK4/6i and PARPi Combination Treatment in RB-Proficient and RB-Deficient Breast Cancer Cells

69 Pages Posted: 7 Nov 2018

See all articles by Songyu Li

Songyu Li

Dalian University - Dalian Medical University

Xiaoyan Wu

Dalian University - Dalian Medical University

Kai Wang

Dalian University - Dalian Medical University

Qi Xiao

Dalian University - Dalian Medical University

Na Wang

Dalian University - Dalian Medical University

Lina Wang

Dalian University - Institute of Cancer Stem Cell

Qingkai Yang

Dalian University - Institute of Cancer Stem Cell

More...

Abstract

DNA damage results in mutations and plays critical roles in cancer development, progression, and treatment. Targeting DNA damage response in cancers by inhibiting poly-(ADP-ribose) polymerases (PARPs) offers an important therapeutic strategy. However, the failure of PARP inhibitors to markedly benefit patients suggests the necessity for developing new strategies to improve their efficacy. Here, we show that the expression of cyclin dependent kinase 4/6 (CDK4/6) complex members significantly correlates with mutations (as proxies of DNA damages), and that the combination of CDK4/6 and PARP inhibitors shows synergy in both RB-proficient and RB-deficient breast cancer cells.  As PARPs constitute sensors of DNA damage and are broadly involved in multiple DNA repair pathways, we hypothesized that the combined inhibition of PARPs and DNA repair (or repair-related) pathways critical for cancer (DRPCC) should show synergy. To identify druggable candidate DRPCC(s), we analyzed the correlation between the genome-wide expression of individual genes and the mutations for 27 different cancer types, assessing 7146 exomes and over 1,500,000 somatic mutations. Pathway enrichment analyses of the top ranked genes correlated with mutations indicated "cell cycle pathway" as the top candidate DRPCC. Additionally, among functional cell-cycle complexes, the CDK4/6 complex showed the most significant negative correlation with mutations, also suggesting that combined CDK4/6 and PARP inhibition might exhibit synergy. Furthermore, combination treatment showed synergy in not only RB-proficient but also RB-deficient breast cancer cells in a reactive oxygen species-dependent manner. These findings suggest a potential therapeutic strategy to improve the efficacy of PARP and CDK4/6 inhibitors in cancer treatment.

Funding: This study was supported by grants from the National Natural Science Foundation of China (NSFC Nos. 31471328 and 81622040 to Q. Yang; 81502622 to L. Wang).

Declaration of Interest: The authors declare that they have no competing interests.

Ethical Approval: The animal-handling procedures were approved by the Animal Care and Use Committee of Dalian Medical University.

Keywords: Pan-cancer analysis; PARP inhibitors; CDK4/6 inhibitors; Breast cancer

Suggested Citation

Li, Songyu and Wu, Xiaoyan and Wang, Kai and Xiao, Qi and Wang, Na and Wang, Lina and Yang, Qingkai, Pan-Cancer Analysis Reveals Synergistic Effects of CDK4/6i and PARPi Combination Treatment in RB-Proficient and RB-Deficient Breast Cancer Cells (May 11, 2018). Available at SSRN: https://ssrn.com/abstract=3279178

Songyu Li

Dalian University - Dalian Medical University

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Xiaoyan Wu

Dalian University - Dalian Medical University

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Kai Wang

Dalian University - Dalian Medical University

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Qi Xiao

Dalian University - Dalian Medical University

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Na Wang

Dalian University - Dalian Medical University

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Lina Wang

Dalian University - Institute of Cancer Stem Cell ( email )

9 Western Lvshun South Road
Dalian, 116044
China

Qingkai Yang (Contact Author)

Dalian University - Institute of Cancer Stem Cell ( email )

9 Western Lvshun South Road
Dalian, 116044
China

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