Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Jan 19

PMID 28099841

Citations 82

Authors

Milica Momcilovic

Sean T Bailey

Jason T Lee

Michael C Fishbein

Clara Magyar

Daniel Braas

Thomas Graeber

Nicholas J Jackson

Johannes Czernin

Ethan Emberley

Matthew Gross

Julie Janes

Andy MacKinnon

Alison Pan

Mirna Rodriguez

Melissa Works

Winter Zhang

Francesco Parlati

Susan Demo

Edward Garon

Kostyantyn Krysan

Tonya C Walser

Steven M Dubinett

Saman Sadeghi

Heather R Christofk

David B Shackelford

Affiliations

Soon will be listed here.

Abstract

Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with F-fluoro-2-deoxyglucose (F-FDG) and C-glutamine (C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with F-FDG and C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.

Citing Articles

Invasion and metastasis in cancer: molecular insights and therapeutic targets.

Li Y, Liu F, Cai Q, Deng L, OuYang Q, Zhang X Signal Transduct Target Ther. 2025; 10(1):57.

PMID: 39979279 PMC: 11842613. DOI: 10.1038/s41392-025-02148-4.

Fuel for thought: targeting metabolism in lung cancer.

Schneider J, Han S, Nabel C Transl Lung Cancer Res. 2025; 13(12):3692-3717.

PMID: 39830762 PMC: 11736591. DOI: 10.21037/tlcr-24-662.

PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma.

Lypova N, Dougherty S, Clem B, Feng J, Yin X, Zhang X Cancer Metab. 2024; 12(1):37.

PMID: 39696407 PMC: 11658331. DOI: 10.1186/s40170-024-00366-y.

Tumor energy metabolism: implications for therapeutic targets.

Hu Y, Liu W, Fang W, Dong Y, Zhang H, Luo Q Mol Biomed. 2024; 5(1):63.

PMID: 39609317 PMC: 11604893. DOI: 10.1186/s43556-024-00229-4.

Eye on the horizon: The metabolic landscape of the RPE in aging and disease.

Hansman D, Du J, Casson R, Peet D Prog Retin Eye Res. 2024; 104:101306.

PMID: 39433211 PMC: 11833275. DOI: 10.1016/j.preteyeres.2024.101306.

References

Krall A, Xu S, Graeber T, Braas D, Christofk H . Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun. 2016; 7:11457. PMC: 4855534. DOI: 10.1038/ncomms11457. View

Qu W, Oya S, Lieberman B, Ploessl K, Wang L, Wise D . Preparation and characterization of L-[5-11C]-glutamine for metabolic imaging of tumors. J Nucl Med. 2011; 53(1):98-105. DOI: 10.2967/jnumed.111.093831. View

Bannai S, Tateishi N . Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol. 1986; 89(1):1-8. DOI: 10.1007/BF01870891. View

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H . Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362(25):2380-8. DOI: 10.1056/NEJMoa0909530. View

Harris I, Treloar A, Inoue S, Sasaki M, Gorrini C, Lee K . Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015; 27(2):211-22. DOI: 10.1016/j.ccell.2014.11.019. View

Khozin S, Blumenthal G, Jiang X, He K, Boyd K, Murgo A . U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist. 2014; 19(7):774-9. PMC: 4077454. DOI: 10.1634/theoncologist.2014-0089. View

Smith N, Baker S, Gonzalez F, Harris J, Figg W, Sparreboom A . Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100. Br J Cancer. 2008; 98(10):1630-2. PMC: 2391127. DOI: 10.1038/sj.bjc.6604353. View

Koppenol W, Bounds P, Dang C . Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011; 11(5):325-37. DOI: 10.1038/nrc3038. View

10.

Wise D, DeBerardinis R, Mancuso A, Sayed N, Zhang X, Pfeiffer H . Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A. 2008; 105(48):18782-7. PMC: 2596212. DOI: 10.1073/pnas.0810199105. View

11.

Liu J, Chen F, Lung J, Lo C, Lee F, Lu Y . Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma. Br J Cancer. 2014; 111(5):944-54. PMC: 4150268. DOI: 10.1038/bjc.2014.355. View

12.

Fendt S, Bell E, Keibler M, Davidson S, Wirth G, Fiske B . Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 2013; 73(14):4429-38. PMC: 3930683. DOI: 10.1158/0008-5472.CAN-13-0080. View

13.

Eng C, Wang Z, Tkach D, Toral-Barza L, Ugwonali S, Liu S . Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc Natl Acad Sci U S A. 2015; 113(1):182-7. PMC: 4711870. DOI: 10.1073/pnas.1515617113. View

14.

Usuda K, Sagawa M, Aikawa H, Ueno M, Tanaka M, Machida Y . Correlation between glucose transporter-1 expression and 18F-fluoro-2-deoxyglucose uptake on positron emission tomography in lung cancer. Gen Thorac Cardiovasc Surg. 2010; 58(8):405-10. DOI: 10.1007/s11748-010-0603-1. View

15.

Hensley C, Wasti A, DeBerardinis R . Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013; 123(9):3678-84. PMC: 3754270. DOI: 10.1172/JCI69600. View

16.

Le A, Lane A, Hamaker M, Bose S, Gouw A, Barbi J . Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15(1):110-21. PMC: 3345194. DOI: 10.1016/j.cmet.2011.12.009. View

17.

Gao P, Tchernyshyov I, Chang T, Lee Y, Kita K, Ochi T . c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009; 458(7239):762-5. PMC: 2729443. DOI: 10.1038/nature07823. View

18.

Wang J, Erickson J, Fuji R, Ramachandran S, Gao P, Dinavahi R . Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18(3):207-19. PMC: 3078749. DOI: 10.1016/j.ccr.2010.08.009. View

19.

Hidalgo M, Siu L, Nemunaitis J, Rizzo J, Hammond L, Takimoto C . Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001; 19(13):3267-79. DOI: 10.1200/JCO.2001.19.13.3267. View

20.

Makinoshima H, Takita M, Matsumoto S, Yagishita A, Owada S, Esumi H . Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma. J Biol Chem. 2014; 289(30):20813-23. PMC: 4110289. DOI: 10.1074/jbc.M114.575464. View