密歇根大学Arul M. Chinnaiyan课题组取得一项新突破。他们报道了靶向PIKfyve驱动的胰腺癌脂质代谢。2025年4月23日出版的《自然》杂志发表了这项成果。

研究组将PIKfyve（溶酶体功能不可或缺的脂质激酶）定性为PDAC的可靶向易感性。使用基因工程motheme模型，该课题组人员确定PIKfyve对PDAC进展至关重要。

此外，通过全面的代谢分析，该研究组发现PIKfyve抑制迫使PDAC上调一个独特的转录和代谢程序，有利于它们重新合成脂质。在PDAC中，KRAS-MAPK信号通路是新生脂质合成的主要驱动因素。因此，同时靶向PIKfyve和KRAS-MAPK在许多临床前人类和非主题模型中消除了肿瘤负担。综上所述，这些研究表明，通过抑制PIKfyve破坏脂质代谢，结合KRAS-MAPK导向的PDAC治疗可诱导合成致死。

据介绍，胰腺导管腺癌（PDAC）存在于营养失调的微环境中，这使得它特别容易受到干扰癌症代谢的治疗的影响。例如，PDAC涉及并依赖于高水平的自噬和其他溶酶体过程。尽管靶向这些途径在临床前研究中显示出潜力，但由于难以确定和描述药物开发的有利靶点，进展一直受到阻碍。

附：英文原文

Title: Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

Author: Cheng, Caleb, Hu, Jing, Mannan, Rahul, He, Tongchen, Bhattacharyya, Rupam, Magnuson, Brian, Wisniewski, Jasmine P., Peters, Sydney, Karim, Saadia A., MacLean, David J., Karabrk, Hseyin, Zhang, Li, Rossiter, Nicholas J., Zheng, Yang, Xiao, Lanbo, Li, Chungen, Awad, Dominik, Mahapatra, Somnath, Bao, Yi, Zhang, Yuping, Cao, Xuhong, Wang, Zhen, Mehra, Rohit, Morlacchi, Pietro, Sahai, Vaibhav, Pasca di Magliano, Marina, Shah, Yatrik M., Weisman, Lois S., Morton, Jennifer P., Ding, Ke, Qiao, Yuanyuan, Lyssiotis, Costas A., Chinnaiyan, Arul M.

Issue&Volume: 2025-04-23

Abstract: Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3,4,5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS–MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS–MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS–MAPK-directed therapies for PDAC.

DOI: 10.1038/s41586-025-08917-z

Source: https://www.nature.com/articles/s41586-025-08917-z