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 2

Cholesterol promotes lung cancer cell survival during targeted therapy.

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Cholesterol promotes lung cancer cell survival during targeted therapy. ...
(A) Relative mRNA levels of SREBP2, HMGCR, and SQLE in PC9, H358, and H3122 cells treated with targeted therapy (gefitinib, sotorasib, and alectinib, respectively). (B) Western blot analysis of HMGCR, SQLE, and FDPS in these cell lines after targeted therapies. (C) Filipin staining of these cell lines after targeted therapies. Scale bar: 10 μm. (Right) Quantification of MFI of filipin. Each dot represents per cell. (D–F) Representative HMGCR and SQLE IHC staining in PC9, H358, and H3122 xenografts. Scale bar: 50 μm. (G and H) Violin plots depicting HMGCR or SQLE expression in scRNA-Seq data from 5 paired clinical samples. (I and J) Representative HMGCR and SQLE IHC staining and H-score quantification in EGFR-mutant clinical samples. Scale bar: 50 μm. Baseline (n = 11); PR plus stable disease (PR+SD) (n = 18); PD (n = 12). (K–M) Viability of PC9 cells treated with gefitinib (Gef) combined with lovastatin (Lova) (0.5–5 μM), BPH652 (50–200 μM) (L), or NB598 (25–100 μM) (M) for 48 hours. (N) Viability of PC9 cells treated with gefitinib, combined with lovastatin (5 μM), or with lovastatin plus squalene (SQ) (0.125, 0.25, or 0.5 μM) or MVA (0.25–1 mM) for 48 hours. (O) Viability of PC9 cells treated with gefitinib, combined with lovastatin, or with lovastatin plus geranylgeranyl pyrophosphate (GGPP) (0.5–2 μM), coenzyme Q9 (CoQ9) (2.5–10 μM), or coenzyme Q10 (CoQ10) (2.5–10 μM) for 48 hours. (P–R) Viability of these cell lines treated with targeted therapies, combined with lovastatin, or with lovastatin plus MβCD-coated cholesterol (Chol) (2.5–10 μg/mL) for 48 hours. Data in A–C and K–R represent 1 representative experiment of 3 independent replicates. 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 (A and J–R); 2-tailed unpaired Student’s t test (C and G–H). Data are reported as mean ± SEM. Ale, alectinib; Sot, sotorasib.