Li Kai-Min, Deng Li-Gong, Xue Li-Jun, Tan Chang, Yao Shu-Kun
School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China.
Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong Province, China.
Heliyon. 2024 Aug 13;10(17):e36283. doi: 10.1016/j.heliyon.2024.e36283. eCollection 2024 Sep 15.
Homologous recombination defects (HRD) render cells fail to repair DNA double-strand break (DSB), which causes synthetic lethality in these cells with punch by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Here, we reveal a receptor tyrosine kinase, AXL, whose inhibition leads to HRD in hepatocellular carcinoma (HCC) cells. AXL is upregulated in HCC tumors, which is positively correlated with low survival rates. AXL knockdown or AXL inhibition by bemcentinib reduces HR efficiency in HCC cells, and AXL plays its role in HR repair through its kinase activity. Furthermore, we find that AXL interacts with RPA2, enhancing the recruitment of RPA2 to DNA damage sites. Mechanistically, AXL promotes the tyrosinization of RPA2 at tyrosine 9, promoting the phosphorylation of CHK1, thereby strengthens the HR repair ability in HCC cells to resist DNA damage. In conclusion, our results reveal that AXL is a promising therapeutic biomarker for HCC patients, and present that targeting AXL-RPA2-CHK1 pathway together with PARP inhibitor will be effective therapeutic strategy in HCC.
同源重组缺陷（HRD）使细胞无法修复DNA双链断裂（DSB），这会导致这些细胞在受到聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）作用时出现合成致死现象。在此，我们揭示了一种受体酪氨酸激酶AXL，其抑制会导致肝癌（HCC）细胞出现HRD。AXL在HCC肿瘤中上调，与低生存率呈正相关。通过贝美替尼敲低AXL或抑制AXL可降低HCC细胞中的HR效率，且AXL通过其激酶活性在HR修复中发挥作用。此外，我们发现AXL与RPA2相互作用，增强RPA2向DNA损伤位点的募集。从机制上讲，AXL促进RPA2在酪氨酸9处的酪氨酰化，促进CHK1的磷酸化，从而增强HCC细胞抵抗DNA损伤的HR修复能力。总之，我们的结果表明AXL是HCC患者有前景的治疗生物标志物，并表明靶向AXL-RPA2-CHK1通路联合PARP抑制剂将是HCC有效的治疗策略。
