Abstract 5707: Augmentation of statin-induced ATF4 stress response enhances the cancer cell-killing effect of statin

Abstract Statins are a class of drugs widely used to reduce cholesterol levels and have been rediscovered as promising anti-cancer drugs. Statins inhibit HMG-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We found that statin treatment of neuroblastoma cells triggered stress responses characterized by upregulation of the master stress regulator ATF4. The primary function of ATF4 is to initiate a gene expression program to mitigate stress and promote cell survival. However, ATF4 can also induce cell death under severe or prolonged stress conditions. Our study revealed that combinations of simvastatin with compounds that amplify ATF4 stress signaling synergistically inhibited the growth and survival of neuroblastoma cells. These compounds include the endoplasmic reticulum (ER) stress sensor ATF6 activator, AA147, and the two ATF4 activators, Sal003 and Nelfinavir. The combination of simvastatin with AA147, Sal003 or Nelfinavir significantly increased ER stress marker, XBP1s, and strongly stimulated ATF4-ATF3-CHOP signaling, leading to apoptosis as evidenced by cleavage of caspase 3 and PARP. Moreover, knocking down ATF4 was able to inhibit apoptosis and partially protect neuroblastoma cells from the effects of these drug combinations. These results suggest a strategy to enhance the anti-tumor effect of statins by amplifying ATF4 stress signaling to trigger apoptosis. Citation Format: Thi Thinh Nguyen, Gia-Buu Tran, Jane Ding, Han-fei Ding. Augmentation of statin-induced ATF4 stress response enhances the cancer cell-killing effect of statin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5707.