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 4

Cholesterol biosynthesis promotes AKT activation.

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Cholesterol biosynthesis promotes AKT activation. (A and B) Representati...
(A and B) Representative IF staining (A) and quantification (B) of p-AKT Ser473 in PC9 cells treated with gefitinib (Gef) for the indicated times. (C and D) Representative IF staining (C) and quantification (D) of p-AKT Ser473 in PC9 cells treated with gefitinib in combination with lovastatin (Lova) (5 μM) for the indicated times. (E and F) Representative IF staining (E) and quantification (F) of p-AKT Ser473 in PC9 cells treated with gefitinib in combination with lovastatin (5 μM) and squalene (SQ) (0.5 μM) for the indicated times. (G and H) Representative IF staining (G) and quantification (H) of p-AKT Ser473 in PC9 cells treated with gefitinib in combination with lovastatin (5 μM) and MβCD-coated cholesterol (10 μg/mL) for the indicated times. (A, C, E, and G) p-AKT is shown in green, and nuclei are stained with DAPI (blue). Scale bar: 10 μm. (I–L) Western blot analysis of p-AKT Ser308 and Ser473 in PC9 cells treated with gefitinib (I), or in combination with lovastatin (5 μM) (J), or in combination with lovastatin (5 μM) and squalene (0.5 μM) (K) or MβCD-coated cholesterol (Chol) (10 μg/mL) (L) for the indicated times. Data represent 1 representative result of 3 independent experiments. GAPDH was used as an internal control. ***P < 0.001 by 1-way ANOVA with Dunnett’s multiple comparisons test (B, D, F, and H). Data are represented as mean ± SEM.