Abdel-Aziz Amal Kamal, Abdel-Naim Ashraf B, Shouman Samia, Minucci Saverio, Elgendy Mohamed
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Front Pharmacol. 2017 Oct 10;8:718. doi: 10.3389/fphar.2017.00718. eCollection 2017.
Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome.
舒尼替尼是一种多酪氨酸激酶抑制剂，目前是转移性肾细胞癌（mRCC）的标准一线治疗药物，也用于治疗胰腺神经内分泌瘤患者以及对伊马替尼耐药的胃肠道间质瘤（GIST）患者。然而，大多数患者最终会因内在或获得性舒尼替尼耐药而复发。据报道，自噬与化疗敏感性和耐药性均有关。然而，在过去几年中，关于舒尼替尼对自噬的调节作用存在争议。由于深入了解潜在的分子机制和临床意义对于实现最佳治疗反应至关重要，这篇综述文章揭示了一个促生存信号通路网络的作用，该网络最近被确定为舒尼替尼耐药的关键介质，具有作为自噬调节因子的既定和新出现的功能。此外，我们强调了舒尼替尼反应性的潜在预后生物标志物，这些标志物可指导临床医生对患者进行分层并实施更个体化的治疗。重要的是，文中讨论了在临床前研究和前瞻性临床试验中评估的克服舒尼替尼耐药的创新治疗策略/方法，这些策略最终可能转化为更好的临床结果。
