Catalano Fabio, Borea Roberto, Puglisi Silvia, Boutros Andrea, Gandini Annalice, Cremante Malvina, Martelli Valentino, Sciallero Stefania, Puccini Alberto
Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy.
Cancers (Basel). 2022 Mar 9;14(6):1388. doi: 10.3390/cancers14061388.
Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15-20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.
近年来，结直肠癌（CRC）治疗取得了重大进展，尤其是在分子驱动疗法和免疫疗法方面。尽管如此，大量晚期结直肠癌患者并未从这些治疗中获益，其预后仍然很差。DNA损伤反应（DDR）改变的情况正成为不同癌症类型治疗的新靶点。聚（ADP-核糖）聚合酶（PARP）抑制剂已被批准用于治疗携带有害致病变体或同源重组修复（HRR）缺陷（HRD）的卵巢癌、乳腺癌、胰腺癌和前列腺癌。最近的研究报道了HRD在CRC中的新作用，并表明这些基因的种系或体细胞改变在高达15%-20%的CRC中存在。然而，HRD的作用仍然广为人知，关于其临床影响的数据很少，尤其是在CRC患者中。在本综述中，我们报告了目前关于CRC中DDR抑制剂的临床前和临床数据。我们还强调了DDR突变对铂类化疗反应的预测作用以及DDR抑制剂的潜在临床作用。需要更多的临床前和临床试验来更好地了解DDR改变对CRC患者的影响以及新型DDR抑制剂的治疗机会。
