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Therapeutic targeting of the mevalonate–geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Nature Cancer volume 3, pages 614–628 (2022)Cite this article

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Abstract

Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)–geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)–RAB7A–autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA–GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.

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Fig. 1: Establishment of chemoresistant SCLC xenograft mouse models.
Fig. 2: Statins suppress chemoresistant SCLC cells by reduction of MVA.
Fig. 3: Statins effectively inhibit chemoresistant SCLC growth.
Fig. 4: Statins function through the GGPS1–RAB7A–autophagy axis.
Fig. 5: Statins overcome acquired chemoresistance in GGPS1high SCLC.
Fig. 6: Statins overcome intrinsic chemoresistance in GGPS1high SCLC.
Fig. 7: Statins plus chemotherapy overcome chemoresistance in SCLC.

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Data availability

RNA-seq data generated have been deposited in the Gene Expression Omnibus under accession no. GSE160241. The 112 human SCLC RNA expression data were derived from the TCGA Research Network: (http://cancergenome.nih.gov/). The dataset derived from this resource that supports the findings of this study is available as follows: 81 specimens from database no. EGAS00001000925 (European Genome–Phenome Archive under the accession code) and 31 specimens from database no. EGAS00001000334 (EBI)6. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.

Code availability

No new algorithms were developed for this manuscript.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 82030083 to H.J. and 82173340 and 81871875 to L.H.); the National Basic Research Program of China (grant nos. 2017YFA0505501 and 2020YFA0803300 to H.J.); the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB19020201 to H.J.); the National Natural Science Foundation of China (grant nos. 81872312, 82011540007 and 31621003 to H.J., 91957120 to S.L., 81402371 to Y.J., 81802279 to H.H. and 81902326 to X.W.); the Basic Frontier Scientific Research Program of Chinese Academy of Science (no. ZDBS-LY-SM006 to H.J.); the International Cooperation Project of Chinese Academy of Sciences (no. 153D31KYSB20190035 to H.J.); Science and Technology Commission of Shanghai Municipality (no. 21ZR1470300 to L.H.); and the Youth Innovation Promotion Association CAS (no. Y919S31371 to X.W.). R.K.T. is supported by the German Research Foundation Deutsche Forschungsgemeinsaft as part of SFB1399 (grant no. 413326622) and by the German Ministry of Science and Education as part of the e:Med program (InCa, grant no. 01ZX1901A). We thank W. Wei, L. Tan, Y. Feng, H. Zhang, F. Li, Y. Gao, X. Liu, C. Xu, D. Gao, L. Zhang and X. He for helpful comments, and X. Jiang, Y. Zhang, Z. Liu and L. Huang for material sharing.

Author information

Author notes

  1. These authors contributed equally: Chenchen Guo, Ruijie Wan, Yayi He.

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

    Chenchen Guo, Ruijie Wan, Jiayu Cao, Ying Qiu, Tengfei Zhang, Qiqi Zhao, Yujuan Jin, Hsin-Yi Huang, Xue Wang, Luonan Chen, Liang Hu & Hongbin Ji

  2. University of Chinese Academy of Sciences, Beijing, China

    Chenchen Guo, Ruijie Wan, Jiayu Cao, Ying Qiu, Tengfei Zhang, Qiqi Zhao, Luonan Chen & Hongbin Ji

  3. Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China

    Yayi He

  4. State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, China

    Shu-Hai Lin & Yujia Niu

  5. School of Life Science and Technology, Shanghai Tech University, Shanghai, China

    Qiqi Zhao, Luonan Chen & Hongbin Ji

  6. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Li Tan

  7. Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany

    Roman K. Thomas

  8. Department of Pathology, Medical Faculty, University Hospital Cologne, Cologne, Germany

    Roman K. Thomas

  9. DKFZ, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany

    Roman K. Thomas

  10. Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA

    Hua Zhang & Kwok-Kin Wong

  11. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Hongbin Ji

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  1. Chenchen Guo
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Contributions

H.J., L.H. and C.G. conceived the idea and designed the experiments. C.G., R.W. and Y.H. performed all experiments and analyzed data. S.-H.L., Y.Q., T.Z., Q.Z., Y.N., Y.J., H.-Y.H., X.W., L.T., R.K.T., H.Z. and K.-K.W. provided technical assistance and contributed intellectually. Y.H. provided human SCLC biopsy specimens. J.C. and L.C. performed bioinformatics analyses. C.G., L.H. and H.J. wrote the manuscript.

Corresponding authors

Correspondence to Liang Hu or Hongbin Ji.

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Extended data

Extended Data Fig. 1 Establishment of chemoresistant SCLC xenograft mouse models.

(a) Representative IHC staining and quantification of γH2AX staining in H82 and H82R tumors treated with or without E/P (n = 9 tissue sections from three mice). (b and c) Representative IHC staining and quantification of CC3 (b) and γH2AX staining (c) in H209 and H209R tumors treated with or without E/P (n = 9 tissue sections from three mice). (d and e) Representative IHC staining and quantification of CC3 (d) and γH2AX staining (e) in H526 and H526R tumors treated with or without E/P (n = 9 tissue sections from three mice). (f and g) Representative IHC staining and quantification of CC3 (f) and γH2AX staining (g) in H146 and H146R tumors treated with or without E/P (n = 9 tissue sections from three mice). (h) Relative viability of H82 and H82R cells treated upon 0.1μM DDP with indicated concentrations of VP16 for 72 hrs (n = 3 cell culture replicates). Data were shown as means. One of three independent experiments was shown. (i) Relative viability of H526 and H526R cells treated with E/P (0.25 μM VP16 & 0.1μM DDP) for 96 hrs (n = 3 cell culture replicates). One of three independent experiments was shown. (j and k) Representative IHC staining and quantification of CC3 (j) and γH2AX staining (k) in H446 tumors treated with or without E/P (n = 9 tissue sections from three mice). (l and m) Representative IHC staining and quantification of CC3 (l) and γH2AX staining (m) in DMS114 tumors treated with or without E/P (n = 9 tissue sections from three mice). (n) Relative viability of H196 cells treated with E/P (0.25 μM VP16 & 0.1μM DDP) in vitro for 96 hrs (n = 3 cell culture replicates). One of three independent experiments was shown. Scale bars: 50 μm (a-g, j-m). Data were shown as mean ± S.E.M (a-g, j-m). Statistical significance was calculated by two-tailed unpaired Student’s t-test (a-g).

Source data

Extended Data Fig. 2 Statin suppresses chemoresistant SCLC growth via reducing MVA.

(a) Top 10 candidates (red) preferentially inhibiting H82R cell viability in comparison to H82 cells (H82R/H82) from the screening of FDA-approved 1971 drug library. Pravastatin (blue) was also shown. (b) Distribution of the putative targets of 256 FDA-approved metabolic drugs categorized by human diseases. (c) Distribution of the putative targets of 256 FDA-approved drugs categorized by metabolism pathways. (d) Work flow of 256 FDA-approved metabolic drug screening. H82R and H82 cells were treated with individual drugs (5 μM) and cell viability was measured after 72 hrs treatment. (e) Volcano plot showing log2 fold change against log10 P value for each drug in H82 and H82R cells (3 independent cell cultures for each drug). Drugs with the preferential inhibition in H82R cells (-log2 ratio of H82R/H82 > 1 and p < 0.05) were shown in red and those with the preferential inhibition in H82 cells (-log2 ratio of H82R/H82 < -0.5 and p < 0.05) were shown in blue. (f) Relative viability of H82 and H82R cells after 72 hrs treatment with increasing concentrations of pravastatin (n = 3 cell culture replicates). One of two independent experiments was shown. (g) Morphology of H82R cells treated with mevastatin (5 μM) for 72 hrs. (h) Western blotting analysis of cPARP, CC3, P27, P21, and PCNA levels in H82 and H82R cells after treatment with mevastatin (5 μM). (i) Western blotting analysis of HMGCR protein levels in 293 T cells with HMGCR overexpression (left) and H82R cells with shRNA-mediated HMGCR knockdown (right). (j) Western blotting analysis of HMGCR protein levels in H82 and H82R cells. (k) Mass spectrometry (MS) analysis of the relative abundance of IPP/DMAPP, GPP, FPP and GGPP in H82 and H82R cells (n = 4 independent cell cultures). Morphology (g) and western blot (h-j) images were representative of three independent experiments with similar results. Arrow indicated Cleaved PARP (h). Actin served as the internal control. Scale bars: 100 μm (g). Data were shown as mean ± S.E.M (k). Statistical significance was calculated by two-tailed unpaired Student’s t-test (e, k).

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Extended Data Fig. 3 Statin effectively inhibits chemoresistant SCLC growth.

(a and b) Relative viability of 4 chemosensitiveand and 4 chemoresistant cell lines treated with E/P (0.25 μM VP16 & 0.1μM DPP) (a) or mevastatin (5 μM) (b) for 96 hrs (n = 3 cell culture replicates per cell line). See also Fig. 3a. (c) Western blotting analysis of cPARP, CC3, P27, P21, and PCNA levels in chemosensitive cell lines (H209, H526) and chemoresistant cell lines (DMS114, H446) treated with mevastatin (Mev) for 72 hrs. (d and e) Relative viability of H209/H209R (d) and H526/H526R (e) treated with mevastatin (5 μM) for 72 hrs (n = 2 cell culture replicates). One of two independent experiments was shown. (f and g) Tumor (f) and mouse (g) weights from mice treated in Fig. 3b. (n = 7 mice per group). (h) Representative images of Ki-67 IHC staining (left) in H82R tumors treated in Fig. 3b. and quantification of Ki-67 H-Score in H82R tumors (right) treated in Fig. 3b. (n = 9 tissue sections from seven mice). (i) Tumor growth of H82R tumor-bearing mice treated with Control (ctrl) (n = 3 mice), E/P (n = 3 mice), simvastatin (Sim) (n = 2 mice), Sim + E/P (n = 3 mice), pitvastatin (Pit) (n = 2 mice) or Pit + E/P (n = 3 mice). (j and k) Tumor (j) and mouse (k) weights from mice treated in (i). (l and m) Tumor (l) and mouse (m) weights from mice treated in Fig. 3e. (n) Representative images of Ki-67 IHC staining (left) in H446 tumors treated in Fig. 3e and quantification of Ki-67 H-Score in H446 tumors (right) treated in Fig. 3e (n = 9 tissue sections from seven mice). Western blot (c) images were representative of three independent experiments with similar results. Arrow indicated Cleaved PARP (c). Actin served as the internal control. Scale bars: 50 μm (h, n). Data were shown as mean ± S.E.M (f-n). Statistical significance was calculated by one-way ANOVA with Dunnett’s multiple comparisons test (f-n).

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Extended Data Fig. 4 GGPP supplementation reverses the statin’s effects.

(a) Schematic of the MVA pathway. The key enzymes are shown in green and their pharmacological inhibitors are shown in red. The MVA downstream pathways are also indicated. (b to d) Relative viability of H82 and H82R cells treated with increasing concentrations of FDPS inhibitors risedronate, or zoledronate, or TH-Z93 (b), FDFT1 inhibitors BHP-652 or ZA (c), SQLE inhibitor NB-598, SOAT1 inhibitor avasimibe, or NPC1L1 inhibitor ezetimibe (d) for 72 hrs (n = 2 cell culture replicates). One of two independent experiments was shown. (e) The relative cell growth of H82 and H82R cells cultured with or without lipoprotein-depleted serum (LPDS) medium (n = 2 cell culture replicates). (f to j) Relative viability of H82 and H82R cells treated with increasing concentrations of 5-lipoxygenase zileuton (f), GSH synthesis inhibitor erastin (g) or BSO (h), ferroptosis inducer ML-162 or RSL-3 (i), farnesyltransferase inhibitor tipifarnib (j) for 72 hrs (n = 2 cell culture replicates). One of two independent experiments was shown. (k) Measurement of OCR in H82 and H82R cells (n = 5 cell culture replicates). (l) Relative viability of H82 and H82R cells treated with increasing concentrations of GGPS1 inhibitor TH-Z145 for 72 hrs (n = 3 cell culture replicates). One of two independent experiments was shown. (m) Western blotting analysis of GGPS1, SQLE and FDFT1 protein levels in H82 and H82R cells. (n) Western blotting analysis of EZH2 and MYC levels in H82 and H82R cells. (o) Relative viability of H82 and H82R cells treated with increasing concentrations of EZH2 inhibitor JQZ5 and MYC inhibitor BAY1238097 for 72 hrs (n = 3 cell culture replicates). One of two independent experiments was shown. (p) Relative viability of H82R cells co-treated with mevastatin (5 μM) alone or plus increasing concentrations of FPP, FFOH, GGPP, GGOH, SQ, coenzyme Q9, coenzyme Q10, or Idebenone for 72 hrs. FFOH: farnesol, the donor of a farnesyl group. SQ: squalene. CoQ9, Q10: Coenzyme Q9, Q10 (n = 2 cell culture replicates). (q and r) Relative viability of H446 (q) and DMS114 cells (r) co-treated with mevastatin (5 μM) alone or plus individual intermediate metabolites (250 mM MVA, 2 μM FPP, 0.1 μM FFOH, 2 μM GGPP, 10 μM GGOH, 0.1 μM SQ, 10 μM CoQ9, 10 μM CoQ10, 1 μM Idebenone). H446 cells (n = 2 cell culture replicates) were treated with 5 μM mevastatin for 72 hrs and the DMS114 cells (n = 3 cell culture replicates) were treated with 10 μM mevastatin for 96 hrs. One of two independent experiments was shown. (s) MS analysis of the relative abundance of MVA, FPP and GGPP in H82R cells co-treated with mevastatin (5 μM) alone or plus individual intermediate metabolites (250 mM MVA or 2 μM GGPP) for 24 hrs (n = 4 independent cell cultures). (t) MS analysis of the relative abundance of MVA (left) and GGPP (right) in H82R cells treated with pravastatin (20 μM) for 24 hrs (n = 4 independent cell cultures). Western blot images (m-n) were representative of three independent experiments with similar results. Actin served as the internal control. Data were shown as mean ± S.E.M (s-t). Statistical significance was calculated by two-tailed unpaired Student’s t-test (s).

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Extended Data Fig. 5 Statin functions through the GGPS1-RAB7A-autophagy axis.

(a) Mean gene expression of various small RAB GTPases (FPKM) in H82R cells from RNA-seq analysis (n = 3 biological independent samples). (b) Relative cell growth of H82R and H82 cells with Dox-induced knockdown of GGPS1 or RAB7A (n = 3 cell culture replicates). Cells were treated with Dox during the entire experiment. Data were shown as means. One of two independent experiments was shown. (c) Compare the viability of H82R (n = 2 cell culture replicates) and H82 (n = 3 cell culture replicates) cells with Dox-induced knockdown of GGPS1 or RAB7A at day 4. One of two independent experiments was shown. (d) Western blotting analysis of P62 and LC3B protein levels in chemosensitive (H209, H526) and chemoresistant (H446, DMS114) cell lines treated with mevastatin (5 μM) for 72 hrs. (e) Western blotting analysis of cPARP and CC3 levels in H82 and H82R cells treated with mevastatin (5 μM) alone or plus GGPP (2 μM) for 72 hrs. (f) Western blotting analysis of cPARP and CC3 levels in H82R cells with Dox-induced knockdown of GGPS1 or RAB7A. (g) Relative cell growth of H446 cells with or without Dox-induced knockdown of GGPS1 or RAB7A (n = 3 cell culture replicates). Data were shown as means. One of two independent experiments was shown. (h) Western blotting analysis of GGPS1, RAB7A, P62 and LC3B levels in H446 cells with Dox-induced knockdown of GGPS1 or RAB7A. (i) Relative viability of H82 and H82R cells with chloroquine (20 μM) or Baf-A1 (2 nM) treatment (n = 2 cell culture replicates). One of two independent experiments was shown. (j) Representative immunofluorescence images indicating the autophagosome in H446 cells expressing mRFP−GFP−LC3 fusion protein in response to mevastatin (5 μM) alone or plus GGPP (2 μM) for 72 hrs treatment. (k) Quantification of RFP+GFP+ and RFP+GFP- puncta in H446 cells treated in (j). (n = 19/14/13 independent cells of Ctrl/ Mev/ Mev+GGPP groups respectively). (l and m) Relative viability of 2 chemosensitive (H209, H526) and 2 chemoresistant cells (H446, DMS114) treated with increasing concentrations of FDPS inhibitor TH-Z93 (l) or GGPS1 inhibitor TH-Z145 (m) for 72 hrs (n = 3 cell culture replicates per cell line). (n) Western blotting analysis of P62 and LC3B levels in chemosensitive (H526) and chemoresistant (DMS114) cells treated with TH-Z145 (0.3 mM). (o) Western blotting analysis of P62 and LC3B levels in H82R tumors treated with mevastatin alone or plus E/P. (p) Relative viability of H82R cells pre-incubated with z-VAD (20 μM) or IETD (20 μM) for 2 hrs then treated with mevastatin (10 μM) 24 hrs (n = 3 cell culture replicates). One of three independent experiments was shown. (q) Western blotting analysis of cPARP, CC8 (cleaved caspase 8) and CC3 levels in H82R cells pre-incubated with z-VAD (20 μM) or IETD (20 μM) for 2 hrs then treated with mevastatin (10 μM) 24 hrs. (r) FACS analysis of relative ROS levels in DMS114 and H526 cells after 48 hrs treatment with E/P or mevastatin (5 μM) treatment (n = 3 independent cell cultures). (s) FACS analysis of relative ROS levels in H82R and H82 cells with Dox-induced knockdown of GGPS1 or RAB7A for 48 hrs (n = 3 independent cell cultures). Western blot (d-f, h, n-o, q) and immunofluorescence (j) results were representative of three independent experiments with similar results. Arrow indicated Cleaved LC3B (d, h, n-o) or Cleaved PARP (e-f, q). Tubulin or Actin served as the internal control. Scale bars: 5μm (j). Data were shown as mean ± S.E.M (k, r-s). Statistical significance was calculated by one-way ANOVA with Dunnett’s multiple comparisons test (k, r-s).

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Extended Data Fig. 6 Knockdown of GGPS1 or RAB7A phenocopied the statin’s effects.

(a) Subcutaneous H82R tumors from mice treated in Fig. 4o. (b) Tumor weights from mice treated in Fig. 4o (n = 5 mice per group). (c) Representative IHC staining of GGPS1 and 8-OXO (c) and quantification of GGPS1-positive cells and 8-OXO H-Score (d) in H82R tumors treated in Fig. 4o (n = 9 tissue sections from five mice). (e) Mouse weights from Fig. 4o (n = 5 mice per group). (f) Tumor growth of H82 tumor-bearing mice with or without inducible GGPS1 knockdown (n = 3 mice per group). (g) Tumor weights from mice treated in (f). (h) Representative IHC staining of GGPS1 in H82 tumors treated in (f). (i) Representative IHC staining of CC3 and quantification of CC3 positive cells in H82 tumors treated in (f) (n = 9 tissue sections from three mice). (j) Tumor growth of H82R tumor-bearing mice with or without inducible RAB7A knockdown (n = 5 mice per group). (k) Subcutaneous H82R tumors from mice treated in (j). (l) Tumor weights from mice treated in (j). (m) Representative H&E and IHC staining of RAB7A, CC3, γH2AX and 8-OXO (m) and quantification of RAB7A, CC3, γH2AX positive cells and 8-OXO H-Score (n) in H82R tumors treated in (j) (n = 6 tissue sections from five mice). (o) Western blotting analysis of P62 and LC3B levels in H82R tumors treated in (j). (p) Relative cell growth of H82R cells with Dox treatment (n = 3 cell culture replicates). Cells were treated with Dox during the entire experiment. Data were shown as means. One of two independent experiments was shown. (q) Tumor growth of H82R tumor-bearing mice with Dox treatment (n = 5 mice per group). (r-s) Tumor (r) and mouse (s) weights from mice treated in (q). Immunohistochemistry (h) and western blot (o) results were representative of three independent experiments with similar results. Arrow indicated Cleaved LC3B (o). Tubulin served as the internal control. Scale bars: 50 μm (c, h-i, m). Data were shown as mean ± S.E.M (b, d-g, i-j, l, n, q-s). Statistical significance was calculated by two-tailed unpaired Student’s t-test (b, d, j, l, n).

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Extended Data Fig. 7 Statins overcome acquired chemoresistance in GGPS1high SCLC.

(a) Western blotting analysis of HMGCR, FDPS, FDFT1 and SQLE levels in chemosensitive and chemoresistant cell lines. (b) MS analysis of the relative abundance of IPP/DMAPP (H446, P < 0.0001; DMS114, P < 0.0001; H196, P < 0.0001), GPP (H446, P < 0.0001; DMS114, P = 0.0747; H196, P = 0.4009) and FPP (H446, P < 0.0001; DMS114, P = 0.0014; H196, P < 0.0001) in chemosensitive and chemoresistant cell lines. Data shown as the relative value of these metabolites in comparison to mevalonate (n = 4 independent cell cultures per cell line). (c and d) Representative IHC and quantification of CC3 (c) and γH2AX staining (d) in SC234 and SC234R tumors treated with or without E/P (n = 9 tissue sections from three mice). (e and f) Representative IHC and quantification of CC3 (e) and γH2AX staining (f) in SC224 and SC224R tumors treated with or without E/P (n = 9 tissue sections from three mice). (g to i) Western blotting analysis of HMGCR, FDPS, GGPS1, FDFT1 and SQLE levels in SC234/SC234R tumors (g), SC256/SC256R tumors (h) and SC224/SC224R tumors (i). (j) Tumor weights from mice treated in Fig. 5i (n = 5 mice per group). (k) Representative IHC and quantification of 8-OXO staining SC234R tumors treated in Fig. 5i (n = 9 tissue sections from five mice). (l and m) Tumor (l) and mouse (m) weights from mice treated in Fig. 5l. (n = 3 mice per group). (n) Representative IHC and quantification of 8-OXO staining SC256R tumors treated in Fig. 5l (n = 9 tissue sections from three mice). (o and p) Tumor (o) and mouse (p) weights from mice treated in Fig. 5o (n = 4 mice per group). (q) Representative IHC and quantification of 8-OXO staining SC224R tumors treated in Fig. 5o (n = 9 tissue sections from four mice). Western blot (a, g-i) results were representative of three independent experiments with similar results. Tubulin served as the internal control. Scale bars: 50 μm (c-f, k, n, q). Data were shown as mean ± S.E.M (b-f, j-q). Statistical significance was calculated by two-tailed unpaired Student’s t-test (b-f) or one-way ANOVA with Dunnett’s multiple comparisons test (j-n).

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Extended Data Fig. 8 GGPS1 levels in SCLC PDX tumors with various drug responses.

(a to c) PDX mouse models were established using transbronchoscopic lung biopsy specimens from treatment-naïve SCLC patients and subjected to E/P treatment. Ticks on the X axis indicated day1 of each E/P cycle. These patients had differential responses to chemotherapy in the clinic: SC022, SC007, SC158 and SC185 had PR (partial response) (a); SC073 and SC441 had SD (stable disease) (b); SC009 had PD (progressive disease) (c). (d to e) Representative IHC staining of NCAM (d) and GGPS1 (e) in various SCLC PDX mouse tumors. PR, partial response; SD, stable disease; PD, progressive disease. Scale bars: 50 μm. Immunohistochemistry results (d-e) were representative of three independent experiments with similar results. Scale bars: 50 μm (d-e). Data were shown as mean ± S.E.M (a-c). Statistical significance was calculated by two-tailed unpaired Student’s t-test (a-c).

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Extended Data Fig. 9 Statins overcome intrinsic chemoresistance in GGPS1high SCLC.

(a) Western blotting analysis of HMGCR level in indicated PDX tumors used in Fig. 6b. (b) Subcutaneous SC009 tumors from mice treated in Fig. 6d. (c and d) Tumor (c) and mouse (d) weights from mice treated in Fig. 6d. (n = 5 mice per group). (e) Representative IHC and quantification of 8-OXO staining of SC009 tumors treated in Fig. 6d (n = 9 tissue sections from five mice). (f and g) Tumor (f) and mouse (g) weights from mice treated in Fig. 6g (n = 5 mice per group). (h) Representative IHC and quantification of 8-OXO staining of SC359 tumors treated in Fig. 6g (n = 9 tissue sections from five mice). (i to k) Survival analysis of SCLC patients according to HMGCR (i), SQLE (j) and FDFT1 (k) expression status in TCGA database. (l) Q-PCR analysis of HMGCR and HMGCS1 levels in H82 and H82R cells treated with mevastatin (5 μM) for 16 hrs. (m) Q-PCR analysis of HMGCR and HMGCS1 levels in H446 and DMS114 cells treated with mevastatin (5 μM) for 16 hrs. (n and o) Q-PCR analysis of HMGCR and HMGCS1 levels in SC009 (n) or SC359 (o) tumors treated with mevastatin. Two samples per group with three replicates. (p) Q-PCR analysis of HMGCR and HMGCS1 levels in H209 and H209R cells treated with mevastatin (5 μM) for 16 hrs. (q) Q-PCR analysis of HMGCR and HMGCS levels in H526 and H526R cells treated with mevastatin (5 μM) for 16 hrs. Results (l-m, p-q) were representative of two independent experiments with similar results with three replicates. Scale bars: 50 μm (e, h). Data were shown as mean ± S.E.M (c-h). Statistical significance was calculated by one-way ANOVA with Dunnett’s multiple comparisons test (c-h).

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Extended Data Fig. 10 Statin plus chemotherapy overcomes chemoresistance in SCLC.

(a) Representative IHC staining of GGPS1 in two transbronchoscopic lung biopsy specimens from SCLC patients relapsed form chemotherapy (SP016 and SP017). Representative tumor cells were indicated by the orange arrows. (b) Patient SP983: CT scan images at baseline and after 4 weeks of simvastatin plus chemotherapy (etoposide/carboplatin). The in situ lung tumor was indicated by the orange arrows. (c) Patient SP772: CT and MRI scan images at baseline and after 9 weeks of simvastatin plus chemotherapy (albumin-bound paclitaxel). Orange arrows indicated tumors. Top panel: in situ primary lung tumor; Middle and bottom panels: two intracranial metastatic tumors. The maximum diameters of two intracranial metastatic lesions were decreased from 1.2 cm to 0.4 cm and 1.0 cm to 0.6 cm, respectively. (d) The PFS comparison of patients with chemotherapy plus simvastatin (n = 2 patients; SP651, SP772) and patients with chemotherapy alone (n = 4 patients; SP112, SP235, SP347, SP509). The PFS calculation was based on the CT scanning at baseline and after the changes of treatment regimens. The SP983 patient was not available for long term monitor. (e) The median PFS from patients relapsed from first-line chemotherapy in previous reports. Nakao et al. analyzed 17 relapsed SCLC patients followed by albumin-bound paclitaxel treatment. Gelsomino et al. analyzed 43 relapsed SCLC patients followed by albumin-bound paclitaxel treatment. Gelsomino et al. analyzed 25 refractory SCLC patients followed by albumin-bound paclitaxel treatment. (f) Routine blood test of hemoglobin (HGB), white blood cell (WBC), absolute number of neutrophils (NEUT#) and platelet (PLT) in the three patients who received simvastatin plus chemotherapy. (g) Biochemical index of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) in the three patients who received simvastatin plus chemotherapy. (h) Biochemical index of urea nitrogen (UREA), creatinine (CREA) in the three patients who received simvastatin plus chemotherapy. (i) Biochemical index of creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB) in the patients who received simvastatin plus chemotherapy. Immunohistochemistry results (a) were representative of three independent experiments with similar results. Scale bars: 50 μm (a). Data were shown as mean ± S.E.M (d-e). Statistical significance was calculated by two-tailed unpaired Student’s t-test (d).

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Supplementary information

Supplementary Information

Supplementary Fig. 1.

Reporting Summary

Supplementary Tables

Supplementary Tables 1. Screening of 1,971 FDA drugs. 2. Screening of 256 FDA drugs. 3.Primer information. 4.PDX information. 5.Compounds and inhibitors. 6. information on human patients.

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Guo, C., Wan, R., He, Y. et al. Therapeutic targeting of the mevalonate–geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer. Nat Cancer 3, 614–628 (2022). https://doi.org/10.1038/s43018-022-00358-1

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