Yang William, Guo Qianyu, Quan Songhua, Chalmers Zachary R, Parker J Brandon, Truica Mihai, Dufficy Mary F, Kerber Megan M, Vasan Karthik, Gupta Dikshat G, Steffeck Adam W T, Pan Hao, Siddiqui Mohammed, Pham H Tran, Schiltz Gary E, Chakravarti Debabrata, Chandel Navdeep S, Abdulkadir Sarki A
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Sci Adv. 2025 Jul 18;11(29):eadw5228. doi: 10.1126/sciadv.adw5228. Epub 2025 Jul 16.
MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8 T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.
MYC是许多侵袭性和难治性癌症的关键驱动因素。我们开发并鉴定了一种名为MYCi975的小分子MYC抑制剂。为了揭示MYC抑制剂的联合策略，我们使用MYCi975进行了全基因组CRISPR筛选。该筛选揭示了在MYC抑制与线粒体复合物I成分的破坏配对时存在显著的合成致死性，但与其他复合物配对时则没有。从机制上讲，MYC抑制降低了氧化磷酸化和糖酵解，触发了复合物I基因的代偿性上调。因此，对复合物I进行基因或药理学靶向可使肿瘤对MYCi975治疗敏感，导致嘌呤分解代谢增加以及CD8 T细胞和巨噬细胞浸润到肿瘤中。此外，一系列复合物I表达较低的肿瘤细胞显示出对MYC的依赖性增加。这些结果表明，对MYC抑制的代谢适应暴露了复合物I处一个可靶向的弱点，并为与新兴的MYC抑制剂联合治疗提供了合理的策略。
