Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
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Research Article Cell biology Metabolism

Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance

Abstract

Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.

Authors

Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji

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Figure 3

PERK/eIF2α signaling contributes to cholesterol biosynthesis triggered by targeted therapy.

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PERK/eIF2α signaling contributes to cholesterol biosynthesis triggered b...
(A) Heatmap based on RNA-Seq data used in Figure 1A showing expression of ER stress signature genes in PC9 cells after gefitinib (Gef) treatment (n = 2 biological replicates/group). (B) Cell death analysis in PC9, H358, and H3122 cells treated with targeted therapies alone or pretreated with tunicamycin (TM) (1 μg/mL) for 48 hours. (C) Western blot analyses of indicated proteins in PC9, H358, and H3122 cells treated with targeted therapies for the indicated times. (D) Fitted pathway activity curves based on quantified expression levels of proteins from (C). The ER stress pathway (red) is represented by p-PERK, p-EIF2α, and GRP78, and the cholesterol biosynthesis pathway (blue) is represented by HMGCR, SQLE, and FDPS. Protein expression values were quantified, and curves were generated using the LOESS method (100) to show temporal trends in pathway activation in PC9, H358, and H3122 cells after treatment with targeted therapies at the indicated times. (E) Western blot analyses of HMGCR, SQLE, and FDPS in cells cotreated with targeted therapies and GSK2606414 (GSK’414) (10 μM) for the indicated times. (F) Real-time PCR detection of SREBP2, HMGCR, and SQLE mRNA levels in PC9 cells treated with gefitinib alone or in combination with integrated stress response inhibitor (ISRIB) (50 or 200 μM) for 48 hours. (G) Relative viability of PC9, H358, and H3122 cells treated with targeted therapies alone, or in combination with GSK’414 (5 μM), 4μ8C (15 μM), or melatonin (Mela) (2 mM) for 48 hours. Data in B, E, F, and G represent 1 representative result of 3 independent experiments. For Western blot analysis, GAPDH served as the internal control. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Dunnett’s multiple comparisons test (F and G); 2-tailed unpaired Student’s t test (B). Data are represented as mean ± SEM. Ale, alectinib; Sot, sotorasib.