Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress.

Jinzhi Lai,Zhanwen Du,Shashank Gorityala,Chunhong Yan,Jinnan Gao,Yan Xu,Shuming Yang,Yao Zhang,Ou Deng,Zhefu Ma,Gonzalo Susana,Junran Zhang,Xiahui Xiong

doi:10.18632/oncotarget.9156

Abstract

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.

Highlights

Radiotherapy (RT) is an effective and commonly employed treatment in the management of more than half of human malignancies, and remains a standard therapeutic modality for breast cancer patients
Increased expression of oncogene and DNA damage response (DDR) proteins are induced in radioresistant breast cancer cells (RBCC)
In contrast to the common paradigm that CHK1 inhibitor can be used as a radiosensitizer, in this study we report that CHK1 inhibitor, as a single agent, can target RBCC via regulation of replication stress (RS) (Figure 7), reducing the growth of tumor cells in vitro and in vivo

Summary

Introduction

Radiotherapy (RT) is an effective and commonly employed treatment in the management of more than half of human malignancies, and remains a standard therapeutic modality for breast cancer patients. Tumors can be intrinsically resistant to RT or develop adaptive response and become resistant. The challenges in breast cancer management are to determine predictive factors that could help to define the subgroups of patients for whom aggressive local therapeutic option is not needed due to their intrinsic resistance, and determine the subgroups of patients who will really benefit from new treatment strategies after failure of RT. Ionizing radiation (IR) kills cells via causing multiple forms of DNA damage. Rad3-related (ATR) kinase and its downstream factor CHK1 are core elements of the DDR during replication stress. ATR/CHK1 signaling is important for the cells survival in response to DNA damage agents that cause RS

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