de Jesus Victor Hugo Fonseca, Mathias-Machado Maria Cecília, de Farias João Paulo Fogacci, Aruquipa Marcelo Porfirio Sunagua, Jácome Alexandre A, Peixoto Renata D'Alpino
Department of Gastrointestinal Medical Oncology, Oncoclínicas, Florianópolis 88015-020, Brazil.
Department of Gastrointestinal Medical Oncology, Oncoclínicas, São Paulo 04538-132, Brazil.
Cancers (Basel). 2023 Oct 17;15(20):5015. doi: 10.3390/cancers15205015.
Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.
胰腺导管腺癌（PDAC）仍然是癌症相关死亡的一个重要原因，预计在未来几年它在癌症负担中所起的作用将更大。尽管科学家和医生共同努力，但在过去几十年里患者的生存率几乎没有提高，这可能是由于所测试的治疗方式缺乏特异性。最近，潜在可靶向分子改变的发现为PDAC的个性化治疗铺平了道路。确实，PDAC分子框架的核心部分开始被揭示。90%的PDAC中存在KRAS突变，多项研究已证明它们在胰腺癌发生过程中起关键作用。最近的研究揭示了不同KRAS突变在预后以及治疗方面的差异，并厘清了KRAS与下游及平行信号通路效应器之间的关系。此外，对其他涉及KRAS介导发病机制的认识，如KRAS剂量和等位基因失衡，有助于拓宽目前关于这种分子改变的知识。最后，KRAS G12C抑制剂最近在胰腺癌患者中进行了测试并取得了相对成功，携带其他突变的KRAS抑制剂正在临床开发中。这些药物目前代表了在这种可怕疾病中取得重大进展的真正希望。
