Jeong Keun-Yeong, Lee Haejun
R&D Center, Metimedi Pharmaceuticals, Incheon 22006, South Korea.
Department of Nuclear Medicine, Gil Medical Center, Incheon 21565, South Korea.
World J Gastrointest Oncol. 2021 Nov 15;13(11):1544-1550. doi: 10.4251/wjgo.v13.i11.1544.
The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages. Furthermore, at advanced stages, there are important challenges to achieve clinical benefit and symptom resolution, even with the use of an expanded spectrum of anticancer drugs. Recently, a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene (BRCA) mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability. Poly (ADP-Ribose) polymerase (PARP) -1 is an enzyme that can regulate intrinsic functions, such as response to DNA damage. Therefore, in an environment where germline mutations in BRCAs (BRCAness) inhibit homologous recombination in DNA damage, resulting in a lack of DNA damage response, a key role of PARP-1 for the adaptation of the genome instability could be further emphasized. Here, we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.
由于胰腺癌通常在晚期才被诊断出来，属于难治性疾病，早期症状难以识别，因此用于治疗胰腺癌的化疗方案仍然有限。此外，在晚期，即使使用范围更广的抗癌药物，实现临床获益和症状缓解也面临重大挑战。最近，乳腺癌易感基因（BRCA）突变导致对传统化疗的敏感性降低，这为在基因组不稳定性增加的框架内克服胰腺癌的耐药性带来了新的视角。聚（ADP-核糖）聚合酶（PARP）-1是一种能够调节内在功能（如对DNA损伤的反应）的酶。因此，在BRCA的种系突变（BRCAness）抑制DNA损伤中的同源重组，导致缺乏DNA损伤反应的环境中，PARP-1对基因组不稳定性适应的关键作用可能会得到进一步强调。在此，我们总结了PARP-1在具有BRCAness表型的胰腺癌基因组不稳定性中的关键功能作用，并列出了PARP-1抑制剂的临床应用和结果，以突出靶向PARP-1活性的重要性。
