Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition.
Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition.
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用于BRCA/PALB2突变的胰腺癌和新兴策略的精密医学，以改善对PARP抑制的治疗反应。
DOI：
10.3390/cancers14040897
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发表时间：
2022-02-11
期刊：
影响因子：
5.2
通讯作者：
Principe DR
中科院分区：
文献类型：
--
作者：
Principe DR
对于功能缺失突变为BRCA1/2或PALB2的一小部分胰腺导管腺癌(PDAC)患者，一线治疗和维持治疗都有显著差异。这些突变导致双链断裂DNA同源重组(HR)的丧失，大大改变了药物的敏感性。在这篇综述中，我们讨论了目前对缺乏HR的PDAC肿瘤的治疗指南，以及新出现的改善这一人群药物反应的策略。我们还强调了这些策略也可能有效的其他患者群体，以及旨在赋予擅长HR修复的肿瘤类似药物敏感性的新策略。预计到2030年，胰腺癌将成为癌症相关死亡的第二大原因。由于患者通常患有晚期疾病，对广谱化疗的反应较差，总体存活率仍为令人沮丧的10%。这凸显了临床上迫切需要为PDAC患者寻找新的治疗方法。精确医学现在是几种难以治疗的癌症组织的标准护理。这些方法包括确定临床上可操作的分子特征，并与适当的靶向治疗相匹配。选择性多聚(ADP-核糖)聚合酶(PARP)抑制剂，如Niraparib、Oruparib、talazoparib、rucaparib和Veliparib，现已被批准用于几种高保真双链断裂同源重组(HR)丢失的癌症，即BRCA1/2、PALB2和其他功能相关基因的有害突变。最近的证据表明，胰腺导管腺癌(PDAC)是最常见和最致命的胰腺癌组织类型，这种突变的存在显著改变了一线化疗和维持治疗的药物反应。在这篇综述中，我们讨论了目前对确认存在HR双链断裂缺陷的PDAC肿瘤的治疗模式，以及在HR缺陷的PDAC中改善对PARP抑制的反应和提高对擅长HR修复的肿瘤的敏感性的新策略。
For the small subset of pancreatic ductal adenocarcinoma (PDAC) patients with loss-of-function mutations to BRCA1/2 or PALB2, both first-line and maintenance therapy differs significantly. These mutations confer a loss of double-strand break DNA homologous recombination (HR), substantially altering drug sensitivities. In this review, we discuss the current treatment guidelines for PDAC tumors deficient in HR, as well as newly emerging strategies to improve drug responses in this population. We also highlight additional patient populations in which these strategies may also be effective, and novel strategies aiming to confer similar drug sensitivity to tumors proficient in HR repair. Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. As patients typically present with advanced disease and show poor responses to broad-spectrum chemotherapy, overall survival remains a dismal 10%. This underscores an urgent clinical need to identify new therapeutic approaches for PDAC patients. Precision medicine is now the standard of care for several difficult-to-treat cancer histologies. Such approaches involve the identification of a clinically actionable molecular feature, which is matched to an appropriate targeted therapy. Selective poly (ADP-ribose) polymerase (PARP) inhibitors such as Niraparib, Olaparib, Talazoparib, Rucaparib, and Veliparib are now approved for several cancers with loss of high-fidelity double-strand break homologous recombination (HR), namely those with deleterious mutations to BRCA1/2, PALB2, and other functionally related genes. Recent evidence suggests that the presence of such mutations in pancreatic ductal adenocarcinoma (PDAC), the most common and lethal pancreatic cancer histotype, significantly alters drug responses both with respect to first-line chemotherapy and maintenance therapy. In this review, we discuss the current treatment paradigm for PDAC tumors with confirmed deficits in double-strand break HR, as well as emerging strategies to both improve responses to PARP inhibition in HR-deficient PDAC and confer sensitivity to tumors proficient in HR repair.
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