Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC
| Autor: | Xiaomin Ma, Yueke Lin, Lihui Zhu, Yeping Cheng, Weiqiang Jing, Xuecheng Shen, Lihui Han, Tao Li, Caiyu Sun, Xiaoting Lv, Dapeng Ma, Min Yang, Yunxue Zhao, Zhenzhi Qin, Gaozhong Xiong, Haocheng Xuan |
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| Rok vydání: | 2022 |
| Předmět: |
Male
Cancer Research Carcinoma Hepatocellular Combination therapy medicine.medical_treatment Dasatinib Poly (ADP-Ribose) Polymerase-1 Synthetic lethality Poly(ADP-ribose) Polymerase Inhibitors Piperazines Targeted therapy Mice chemistry.chemical_compound PARP1 Mice Inbred NOD Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Animals Humans Medicine Dimethyl Sulfoxide Phosphorylation Zebrafish business.industry Liver Neoplasms Tyrosine phosphorylation Hep G2 Cells Xenograft Model Antitumor Assays digestive system diseases Up-Regulation Disease Models Animal Adenosine diphosphate src-Family Kinases Oncology chemistry Cancer research Phthalazines business Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Cancer Letters. 526:180-192 |
| ISSN: | 0304-3835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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