Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress
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Yao Zhang1,2,*, Jinzhi Lai1,*, Zhanwen Du1, Jinnan Gao2, Shuming Yang3, Shashank Gorityala4, Xiahui Xiong1, Ou Deng1,5, Zhefu Ma5, Chunhong Yan6, Gonzalo Susana7, Yan Xu3,4, Junran Zhang1
1Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
2Department of Breast Surgery, Shanxi Academy of Medical Sciences, The Affiliated Shanxi Dayi Hospital of Shanxi Medical University, Shanxi, 030032, PR China
3Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
4Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA
5Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China
6Augusta University, Augusta, 30912, GA, USA
7Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA
*These authors contributed equally to this work
Junran Zhang, email: [email protected]
Keywords: double strand break repair, homologous recombination, replication stress, CHK1 inhibitor, radioresistance
Received: January 28, 2016 Accepted: April 11, 2016 Published: May 04, 2016
Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells.
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