Kawalerski Ryan R, Leach Steven D, Escobar-Hoyos Luisa F
Medical Scientist Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Departments of Molecular and Systems Biology, Surgery, and Medicine, Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Lebanon, NH 03766, USA.
Oncotarget. 2021 Mar 16;12(6):525-533. doi: 10.18632/oncotarget.27901.
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, has one of the highest case fatality rates of all known solid malignancies. Over the past decade, several landmark studies have established mutations in and as the predominant drivers of PDAC pathogenesis and therapeutic resistance, though treatment options for PDACs and other tumors with these mutations remain extremely limited. Hampered by late tumor discovery and diagnosis, clinicians are often faced with using aggressive and non-specific chemotherapies to treat advanced disease. Clinically meaningful responses to targeted therapy are often limited to the minority of patients with susceptible PDACs, and immunotherapies have routinely encountered roadblocks in effective activation of tumor-infiltrating immune cells. Alternative RNA splicing (ARS) has recently gained traction in the PDAC literature as a field from which we may better understand and treat complex mechanisms of PDAC initiation, progression, and therapeutic resistance. Here, we review PDAC pathogenesis as it relates to fundamental ARS biology, with an extension to implications for PDAC patient clinical management.
胰腺导管腺癌（PDAC）是胰腺癌最常见的组织学亚型，在所有已知实体恶性肿瘤中，其病死率位居前列。在过去十年中，多项具有里程碑意义的研究已证实，KRAS和BRAF突变是PDAC发病机制和治疗耐药性的主要驱动因素，不过针对携带这些突变的PDAC及其他肿瘤的治疗选择仍然极为有限。由于肿瘤发现和诊断较晚，临床医生常常只能使用激进且非特异性的化疗方法来治疗晚期疾病。对靶向治疗具有临床意义的反应通常仅限于少数对治疗敏感的PDAC患者，而且免疫疗法在有效激活肿瘤浸润免疫细胞方面常常遇到阻碍。替代性RNA剪接（ARS）最近在PDAC文献中受到关注，作为一个领域，我们或许可以从中更好地理解和治疗PDAC发生、发展及治疗耐药性的复杂机制。在此，我们回顾与基础ARS生物学相关的PDAC发病机制，并延伸探讨其对PDAC患者临床管理的意义。
