Department of pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Biochem Biophys Res Commun. 2020 Jan 29;522(1):121-126. doi: 10.1016/j.bbrc.2019.11.050. Epub 2019 Nov 18.
Lung cancer is the leading cause of cancer death worldwide. PARP inhibitors have become a new line of cancer therapy and a successful demonstration of the synthetic lethality concept. The mechanism and efficacy of PARP inhibitors have been well studied in some cancers, especially homologous recombination (HR)-deficient ovarian cancer and breast cancer, yet such studies are still relatively fewer in lung cancer. Here we found that HR genes are frequently mutated in lung cancer patients, exposing a window for targeted therapies by PARP inhibitors. We depleted BRCA1 and BRCA2 in non-small cell lung cancer (NSCLC) cancer cells and found these cells are hypersensitive to the PARP inhibitor olaparib in cell viability and clonogenic survival assays. Olaparib specifically induces apoptosis in A549 cells with BRCA1 or BRCA2 depletion, as determined by positive Annexin-V staining. In addition, we show that A549 cells with ATM shRNA knockdown are also hypersensitive to Olaparib. In summary, our data support the potential use of PARP inhibitors in NSCLC with HR deficiency.
肺癌是全球癌症死亡的主要原因。PARP 抑制剂已成为癌症治疗的新方法，成功地证明了合成致死的概念。PARP 抑制剂的机制和疗效已在一些癌症中得到了很好的研究，特别是同源重组（HR）缺陷型卵巢癌和乳腺癌，但在肺癌中的研究仍然相对较少。在这里，我们发现 HR 基因在肺癌患者中经常发生突变，为 PARP 抑制剂的靶向治疗提供了一个机会。我们在非小细胞肺癌（NSCLC）癌细胞中耗尽 BRCA1 和 BRCA2，发现这些细胞在细胞活力和集落存活测定中对 PARP 抑制剂奥拉帕尼高度敏感。奥拉帕尼特异性地诱导 BRCA1 或 BRCA2 耗竭的 A549 细胞凋亡，这可以通过阳性 Annexin-V 染色来确定。此外，我们还表明，用 ATM shRNA 敲低的 A549 细胞对奥拉帕尼也很敏感。总之，我们的数据支持 HR 缺陷型 NSCLC 中使用 PARP 抑制剂的潜力。
