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 5

Dormant cancer cells have high levels of cholesterol and AKT activation.

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Dormant cancer cells have high levels of cholesterol and AKT activation....
(A) Western blot analysis of p21 and p27 in PC9, H358, and H3122 cells treated with targeted therapies. (B) Representative IF images of mcherry-p27K (red) and DAPI (blue) in these cell lines after exposure to targeted therapies. Scale bar: 10 μm. (C) Quantification of MFI of mcherry-p27K from (B). (D) Filipin staining in cells expressing mcherry-p27K after targeted therapies. Scale bars: 10 μm. (E) Schematic illustration of the in vitro experimental design. (F) Representative IF images of cells co-expressing mcherry-p27K (red) and AKT-KTR (cyan) or ERK-KTR (green) for the indicated times. Scale bars: 10 μm. (G and H) AKT (G) or ERK (H) pathway activity, measured as the AKT/ERK-KTR cytoplasmic-to-nuclear intensity ratio (cyto/nuc) from (F). A higher ratio indicates greater pathway activity. (I) Schematic illustration of the xenograft study design. Mice bearing tumors from cells co-expressing mcherry-p27K and AKT/ERK-KTR were treated daily with targeted therapy (25 mg/kg gefitinib [Gef], 30 mg/kg sotorasib {Sot], or 30 mg/kg alectinib [Ale]) alone or in combination with 10 mg/kg lovastatin [Lova]. (J) Representative IF images of xenograft tissue showing staining with mCherry-p27K (red), AKT-KTR (cyan), ERK-KTR (green), and DAPI (blue). Scale bar: 10 μm. (K) Quantification of mCherry-p27K MFI from (J). (L and M) AKT (L) or ERK (M) pathway activity in xenografts, measured as the AKT/ERK-KTR cytoplasmic-to-nuclear ratio from (J). Data in A, B, D, F, and J represent 1 representative result of 3 independent experiments. Fluorescence intensity was analyzed using Image J. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Dunnett’s multiple comparisons test (G, H, and K–M); 2-tailed unpaired Student’s t test (C). Data are represented as mean ± SEM. Ctrl, control.