2. Academic Validation
  3. Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC

Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC

  • Cancer Lett. 2022 Feb 1:526:180-192. doi: 10.1016/j.canlet.2021.11.005.
Caiyu Sun 1,  Weiqiang Jing 2,  Gaozhong Xiong 3,  Dapeng Ma 4,  Yueke Lin 4,  Xiaoting Lv 4,  Yunxue Zhao 5,  Xiaomin Ma 4,  Lihui Zhu 6,  Xuecheng Shen 4,  Min Yang 4,  Zhenzhi Qin 4,  Yeping Cheng 4,  Haocheng Xuan 4,  Tao Li 7,  Lihui Han 8
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Infection and Immunology, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Jinan, 250012, China.
  • 2 Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 3 Shandong Provincial Key Laboratory of Infection and Immunology, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 4 Shandong Provincial Key Laboratory of Infection and Immunology, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 6 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 7 Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 8 Shandong Provincial Key Laboratory of Infection and Immunology, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Jinan, 250012, China. Electronic address: [email protected].
PMID: 34762994 DOI: 10.1016/j.canlet.2021.11.005
Abstract

Hepatocellular carcinoma (HCC), a heterogeneous Cancer with high mortality, is resistant to single targeted therapy; thus, combination therapy based on synthetic lethality is a promising therapeutic strategy for HCC. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) is the most recognized target for synthetic lethality; however, the therapeutic effect of PARP1 inhibition on HCC is disappointing. Therefore, exploring new synthetic lethal partners for the efficient manipulation of HCC is urgently required. In this study, we identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy produced significant anti-tumor effects without causing obvious side effects. Mechanistically, Src interacted with PARP1 and phosphorylated PARP1 at the Y992 residue, which further mediated resistance to PARP1 inhibition. Overall, this study revealed that Src-mediated PARP1 phosphorylation induced HCC resistance to PARP1 inhibitors and indicated a therapeutic window of the Y992 phosphorylation of PARP1 for HCC patients. Moreover, synthetic lethal therapy by co-targeting PARP1 and Src have the potential to broaden the strategies for HCC and might benefit HCC patients with high Src activation and resistance to PARP1 inhibitors alone.

Keywords

Combination therapy; Drug resistance; Hepatocellular carcinoma; PARP1 inhibitors; Synthetic lethality; Tumor resistance.

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