Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2

  • Cell Death Dis. 2022 Feb 10;13(2):138. doi: 10.1038/s41419-022-04590-6.
Xin Zhang   #  1  2 ,  Tao Li   #  2 ,  Mengdi Yang  2 ,  Qianming Du  3  4 ,  Rui Wang  2 ,  Bin Fu  2 ,  Yingying Tan  2 ,  Mengran Cao  2 ,  Yaxin Chen  2 ,  Qing Wang  5 ,  Rong Hu  6
Affiliations
  • 1. State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
  • 2. State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 3. General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4. General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China.
  • 5. Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 6. State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 35145081 DOI: 10.1038/s41419-022-04590-6
Abstract

It was reported that MGMTlow gliomas may still be resistant to TMZ, while the mechanisms remain poorly understood. In this study, we demonstrated that rho-associated kinase 2 (ROCK2), a Cytoskeleton regulator, was highly expressed in MGMTlow recurrent gliomas, and its expression strongly correlated with poor overall survival (OS) time in a subset of MGMTlow recurrent gliomas patients with TMZ therapy. And we also found that overactive ROCK2 enhanced homologous recombination repair (HR) in TMZ-resistant (TMZ-R) glioma cell lines with low MGMT expression. Silencing ROCK2 impaired HR repair, and induced double-strand break (DSB) and eradicated TMZ-R glioma cells in culture. Notably, in MGMTlow TMZ-R models, as a key factor of HR, ataxia telangiectasia-mutated (ATM) expression was upregulated directly by hyper-activation of ROCK2 to improve HR efficiency. ROCK2 enhanced the binding of transcription factor zinc finger E-box binding homeobox 1 (ZEB1) to ATM promoter for increasing ATM expression. Moreover, ROCK2 transformed ZEB1 into a gene activator via Yes-associated protein 1 (YAP1). These results provide evidence for the use of ROCK inhibitors in the clinical therapy for MGMTlow TMZ-resistant glioma. Our study also offered novel insights for improving therapeutic management of MGMTlow gliomas.

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