Nedaeinia Reza, Avan Amir, Manian Mostafa, Salehi Rasoul, Ghayour-Mobarhan Majid
Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 99199-91766, Iran.
Curr Drug Targets. 2014;15(14):1293-301. doi: 10.2174/1389450115666141125123003.
Pancreatic Ductal Adenocarcinoma (PDAC) is among the most lethal solid tumors with grim prognosis. This dismal outcome can partially be explained by the resistance to currently available chemotherapy regimens or the failure of most anticancer agents, which prompted the development of new and effective therapeutic-approaches, such as inhibitors of the epidermal growth factor receptor (EGFR). Some of these EGFR inhibitors (e.g., erlotinib) are approved for lungcancer, however available data are inconclusive for treatment of pancreatic cancer patients with EGFR-targeted-therapies. Here we describe the critical role of EGFR pathway in pancreatic-cancer, strategies to enhance the effectiveness of EGFRinhibitors as well as the preclinical/clinical studies with particular emphasis on recent findings with monoclonal antibodies and tyrosine-inhibitors. Several combinations of EGFR inhibitors with other agents illustrate inhibition of tumor-induced angiogenesis and cell growth. Moreover, combination of erlotinib with gemcitabine showed statistically significance in overall-survival, compared to gemcitabine-alone. However high cost, little survival gain and increased risk of toxicities have limited its efficacy. Considering the multiple genetic mutations and the crosstalk of signaling pathways, (1) development of multiple targeted-therapies; (2) identification of predictive-biomarkers; and (3) those patients who are most likely benefit from therapy, could provide valuable direction for the clinical development of EGFR inhibitors. Moreover further preclinical/clinical studies are warranted to identify determinants of the activity of EGFR-inhibitors and mechanisms leading to resistance to EGFR inhibitors, through the analysis of genetic and environmental alterations affecting EGFR and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current anticancer strategies targeting EGFR in pancreatic cancer.
胰腺导管腺癌（PDAC）是最致命的实体瘤之一，预后严峻。这种令人沮丧的结果部分可以归因于对现有化疗方案的耐药性或大多数抗癌药物的失效，这促使了新的有效治疗方法的开发，例如表皮生长因子受体（EGFR）抑制剂。其中一些EGFR抑制剂（如厄洛替尼）已被批准用于治疗肺癌，然而，关于EGFR靶向治疗胰腺癌患者的数据尚无定论。在这里，我们描述了EGFR通路在胰腺癌中的关键作用、增强EGFR抑制剂有效性的策略以及临床前/临床研究，特别强调了单克隆抗体和酪氨酸抑制剂的最新发现。EGFR抑制剂与其他药物的几种联合应用显示出对肿瘤诱导的血管生成和细胞生长的抑制作用。此外，与单独使用吉西他滨相比，厄洛替尼与吉西他滨联合使用在总生存期方面具有统计学意义。然而，高成本、生存获益甚微以及毒性风险增加限制了其疗效。考虑到多种基因突变和信号通路的相互作用，（1）开发多种靶向治疗；（2）识别预测性生物标志物；（3）确定最可能从治疗中获益的患者，可为EGFR抑制剂的临床开发提供有价值的指导。此外，有必要通过分析影响EGFR和并行促癌通路的基因和环境改变，进一步开展临床前/临床研究，以确定EGFR抑制剂活性的决定因素和导致对EGFR抑制剂耐药的机制。这些研究对于提高当前针对胰腺癌EGFR的抗癌策略的疗效和选择性至关重要。
