Zeitouni Daniel, Pylayeva-Gupta Yuliya, Der Channing J, Bryant Kirsten L
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cancers (Basel). 2016 Apr 18;8(4):45. doi: 10.3390/cancers8040045.
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an "undruggable" protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient's immune system to fight their cancer is an additional exciting route that is being considered. The "best" path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS.
胰腺导管腺癌（PDAC）是最致命的癌症之一，5年生存率低至7%，预计到2020年将成为癌症相关死亡的第二大主要原因。95%的PDAC中KRAS基因发生突变，是PDAC生长和维持的有效驱动因素。然而，尽管进行了全面的努力，一种有效的抗RAS药物尚未进入临床。目前正在研究不同的抑制RAS信号传导的途径，希望找到一种成功的治疗方法。最近，已经发现了直接与RAS结合的分子，这挑战了RAS是一种“不可成药”蛋白质的观念。目前正在探索的其他策略采用间接方法，靶向促进RAS膜结合或下游效应信号传导的蛋白质。无偏向性基因筛选已经确定了突变型RAS的合成致死相互作用分子。最近，与糖酵解信号传导、谷氨酰胺利用、自噬和巨胞饮作用相关的途径中的代谢靶点也在被探索。利用患者的免疫系统对抗癌症是另一条正在被考虑的令人兴奋的途径。抑制KRAS的“最佳”途径尚未确定，每种途径都有希望，但也有潜在的陷阱。我们将总结每个方向的最新进展，重点关注针对携带KRAS突变的胰腺癌患者开发治疗方法的努力。
