Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Cancer Res. 2019 Feb 15;79(4):819-829. doi: 10.1158/0008-5472.CAN-18-1273. Epub 2018 Dec 20.
PARP1 inhibitors (PARPi) are currently used in the clinic for the treatment of ovarian and breast cancers, yet their therapeutic efficacy against hepatocellular carcinoma (HCC) has been disappointing. To ensure therapeutic efficacy of PARPi against HCC, a disease often diagnosed at intermediate to advanced stages with no effective treatment options, it is critical to identify not only biomarkers to predict PARPi resistance but also rational treatments to overcome this. Here, we report that a heterodimer of EGFR and MET interacts with and phosphorylates Y907 of PARP1 in the nucleus, which contributes to PARPi resistance. Inhibition of both EGFR and MET sensitized HCC cells to PARPi, and both EGFR and MET are known to be overexpressed in HCC. This report provides an explanation for the poor efficacy of PARPi against HCC and suggests combinatorial treatment consisting of EGFR, MET, and PARP inhibitors may be an effective therapeutic strategy in HCC. SIGNIFICANCE: Regulation of PARP by the c-MET and EGFR heterodimer suggests a potentially effective combination therapy to sensitize HCC to PARPi.
聚腺苷二磷酸核糖聚合酶 1 抑制剂（PARPi）目前被用于治疗卵巢癌和乳腺癌，但它们在治疗肝细胞癌（HCC）方面的疗效令人失望。为了确保 PARPi 对 HCC 的治疗效果，HCC 常常在中晚期被诊断出来，而且没有有效的治疗方法，因此，不仅要识别预测 PARPi 耐药的生物标志物，还要找到合理的治疗方法来克服这一问题，这一点至关重要。在这里，我们报告 EGFR 和 MET 的异二聚体在细胞核中相互作用并磷酸化 PARP1 的 Y907，这有助于 PARPi 耐药。抑制 EGFR 和 MET 均可使 HCC 细胞对 PARPi 敏感，而 HCC 中已知 EGFR 和 MET 过表达。这一发现为 PARPi 治疗 HCC 效果不佳提供了一种解释，并提示 EGFR、MET 和 PARP 抑制剂的联合治疗可能是 HCC 的一种有效治疗策略。意义：c-MET 和 EGFR 异二聚体对 PARP 的调节提示一种潜在有效的联合治疗方法，可以使 HCC 对 PARPi 敏感。
