REFERENCES
1. Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, et al. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer 2018;17:48.
2. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res 2019;144:19-50.
3. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sánchez V, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Pro Natl Acad Sci USA 2011;108:5021-6.
4. Canfield K, Li J, Wilkins OM, Morrison MM, Ung M, et al. Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell Cycle 2015;14:648-55.
5. Polli JW, Humphreys JE, Harmon KA, Castellino S, O’mara MJ, et al. The role of efflux and uptake transporters in N-{3-chloro-4-[(3-fluorobenzyl) oxy] phenyl}-6-[5-({[2-(methylsulfonyl) ethyl] amino} methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos 2008;36:695-701.
6. Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, et al. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 2009;21:255-62.
7. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941-53.
8. Brünner-Kubath C, Shabbir W, Saferding V, Wagner R, Singer CF, et al. The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells. Breast Cancer Res Treat 2011;129:387-400.
9. Joly MM, Hicks DJ, Jones B, Sanchez V, Estrada MV, et al. Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res 2016;76:4752-64.
10. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68:9221-30.
11. Brady SW, Zhang J, Seok D, Wang H, Yu D. Enhanced PI3K p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective PI3K inhibitor. Mol Cancer Ther 2014;13:60-70.
13. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 2016;5:e189.
14. Liu Q, Luo Q, Halim A, Song G. Targeting lipid metabolism of cancer cells: a promising therapeutic strategy for cancer. Cancer Lett 2017;401:39-45.
15. Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, et al. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res 2013;52:585-9.
16. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 2018;27:136-50.
17. Chen CL, Kumar DB, Punj V, Xu J, Sher L, et al. NANOG metabolically reprograms tumor-initiating stem-like cells through tumorigenic changes in oxidative phosphorylation and fatty acid metabolism. Cell Metab 2016;23:206-19.
18. Feng WW, Wilkins O, Bang S, Ung M, Li J, et al. CD36-mediated metabolic rewiring of breast cancer cells promotes resistance to HER2-targeted therapies. Cell Rep 2019;29:3405-20.
19. Wang Q, Liu P, Spangle JM, Von T, Roberts TM, et al. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2016;35:3607.
20. Krycer JR, Sharpe LJ, Luu W, Brown AJ. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 2010;21:268-76.
21. Wang C, Yan Y, Hu L, Zhao L, Yang P, et al. Rapamycin-mediated CD36 translational suppression contributes to alleviation of hepatic steatosis. Biochem Biophys Res Commun 2014;447:57-63.
22. Yue S, Li J, Lee SY, Lee HJ, Shao T, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 2014;19:393-406.
23. Fazolini NP, Cruz AL, Werneck MB, Viola JP, Maya-Monteiro CM, et al. Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation. Cell Cycle 2015;14:2667-76.
24. Sipula IJ, Brown NF, Perdomo G. Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metabolism 2006;55:1637-44.
25. Brown NF, Stefanovic-Racic M, Sipula IJ, Perdomo G. The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metabolism 2007;56:1500-7.
26. Puig T, Aguilar H, Cufí S, Oliveras G, Turrado C, et al. A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines. Breast Cancer Res 2011;13:R131.
27. Blancafort A, Giró-Perafita A, Oliveras G, Palomeras S, Turrado C, et al. Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs. PLoS One 2015;10:e0131241.
28. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
29. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012;9:16.
30. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 1996;16:5276-87.
31. Xia W, Liu LH, Ho P, Spector NL. Truncated ErbB2 receptor (p95 ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004;23:646.
32. Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, et al. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 2005;24:6213.
33. O’Donovan N, Byrne AT, O’Connor AE, McGee S, Gallagher WM, et al. Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Invest New Drugs 2011;29:752-9.
34. Blackwell KL, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, et al. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first-or second-line trastuzumab-containing regimens. Ann Oncol 2009;20:1026-31.
35. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43.
36. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;112:533-43.
37. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, De Azambuja E, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40.
38. Lin NU, Diéras V, Paul D, Lossignol D, Christodoulou C, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009;15:1452-9.
39. Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinib-mediated growth inhibition of HER 2-amplified cancer cells. Cancer Sci 2013;104:1618-25.
40. Leung WY, Roxanis I, Sheldon H, Buffa FM, Li JL, et al. Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer. Oncotarget 2015;6:5678.
41. Komurov K, Tseng JT, Muller M, Seviour EG, Moss TJ, et al. The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ErbB2-positive breast cancer cells. Mol Syst Biol 2012;8:596.
42. Ruprecht B, Zaal EA, Zecha J, Wu W, Berkers CR, et al. Lapatinib resistance in breast cancer cells is accompanied by phosphorylation-mediated reprogramming of glycolysis. Cancer Res 2017;77:1842-53.
43. Deblois G, Smith HW, Tam IS, Gravel SP, Caron M, et al. ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer. Nat Commun 2016;7:12156.
44. Yang L, Li Y, Shen E, Cao F, Li L, et al. NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells. Int J Oncol 2017;51:1553-62.
45. Zhao Y, Liu H, Liu Z, Ding Y, LeDoux SP, et al. Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Res 2011;71:4585-97.
46. Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010;28:1301-7.
47. Conlon N, Browne A, Breen L, Lowry M, O’Driscoll L, et al. 64P The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models. Ann Oncol 2019;30:mdz238-062.
48. Sudhan DR, Guerrero-Zotano A, Won H, Ericsson PG, Servetto A, et al. Hyperactivation of Torc1 Drives Resistance to the Pan-Her Tyrosine Kinase Inhibitor Neratinib in Her2-Mutant Cancers. Cancer Cell ; doi: 10.2139/ssrn.3362256.
49. Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, et al. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clin Cancer Res 2011;17:1147-59.
50. Ring A, Wheatley D, Hatcher H, Laing R, Plummer R, et al. Phase I study to assess the combination of afatinib with trastuzumab in patients with advanced or metastatic HER2-positive breast cancer. Clin Cancer Res 2015;21:2737-44.
53. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501-12.
54. Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 2010;29:4018.
55. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 2016;13:417.
56. Portman N, Alexandrou S, Carson E, Wang S, Lim E, et al. Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. Endocr Relat Cancer 2019;26:R15-30.
57. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16:25-35.
58. Finn RS, Martin M, Rugo HS, Jones S, Im SA, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925-36.
59. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-39.
60. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11:R77.
61. Kenny FS, Hui R, Musgrove EA, Gee JM, Blamey RW, et al. Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin Cancer Res 1999;5:2069-76.
62. Sabbah M, Courilleau D, Mester J, Redeuilh G. Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci U S A 1999;96:11217-22.
63. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011;11:558.
64. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-49.
65. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 2016;76:2301-13.
66. Zhang J, Xu K, Liu P, Geng Y, Wang B, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Molecular Cell 2016;62:929-42.
67. Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer 2017;3:39-55.
68. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep 2016;14:979-90.
69. Costa C, Wang Y, Ly A, Hosono Y, Ellen M, et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov 2019; doi: 10.1158/2159-8290.CD-18-0830.
71. Michaloglou C, Crafter C, Siersbaek R, Delpuech O, Curwen JO, et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer. Mol Cancer Ther 2018;17:908-20.
72. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget 2014;5:6512.
73. Yang C, Li Z, Bhatt T, Dickler M, Giri D, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 2017;36:2255.
74. Caldon CE, Sergio CM, Kang J, Muthukaruppan A, Boersma MN, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther 2012;11:1488-99.
75. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-38.
76. Condorelli R, Spring L, O’Shaughnessy J, Lacroix L, Bailleux C, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol 2017;29:640-5.
77. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550.
78. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004;3:772-5.
79. Lee JW, Soung YH, Kim SY, Lee HW, Park WS, et al. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 2005;24:1477.
80. Nahta R, O’Regan RM. Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin breast cancer 2010;10:S72-8.
81. Miller TW, Hennessy BT, González-Angulo AM, Fox E, Mills GB, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010;120:2406-13.
82. Esposito A, Viale G, Curigliano G. Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: a review. JAMA Oncol 2019; doi: 10.1001/jamaoncol.2019.0034.
83. Greenwell IB, Ip A, Cohen JB. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park) 2017;31:821-8.
84. Juric D, Castel P, Griffith M, Griffith OL, Won HH, et al. Convergent loss of PTEN leads to clinical resistance to a PI (3) Kα inhibitor. Nature 2015;518:240.
85. Nakanishi Y, Walter K, Spoerke JM, O’Brien C, Huw LY, et al. Activating mutations in PIK3CB confer resistance to PI3K inhibition and define a novel oncogenic role for p110β. Cancer Res 2016;76:1193-203.
86. Huw LY, O’Brien C, Pandita A, Mohan S, Spoerke JM, et al. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer. Oncogenesis 2013;2:e83.
87. Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA 2012;109:2718-23.
88. Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer 2018;18:744-57.
89. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013;153:840-54.
90. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 2008;68:1003-11.
91. Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 2007;18:1437-46.
92. Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol 2009;19:R1046-52.
93. Tran Q, Lee H, Park J, Kim SH, Park J. Targeting cancer metabolism-revisiting the Warburg effects. Toxicol Res 2016;32:177.
94. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14.
95. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007;7:763-77.
96. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nature Reviews Cancer 2016;16:732.
97. Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 2006;66:5977-80.
98. Ookhtens MU, Kannan RA, Lyon IR, Baker NO. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol Regul Integr Comp Physiol 1984;247:R146-53.
99. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA 2013;110:8882-7.
100. Alo PL, Visca P, Marci A, Mangoni A, Botti C, et al. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 1996;77:474-82.
101. Wang YY, Kuhajda FP, Li JN, Pizer ES, Han WF, et al. Fatty acid synthase (FAS) expression in human breast cancer cell culture supernatants and in breast cancer patients. Cancer Lett 2001;167:99-104.
102. Alo PL, Amini M, Piro F, Pizzuti L, Sebastiani V, et al. Immnunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. Anticancer Res 2007;27:2523-7.
103. Cai Y, Wang J, Zhang L, Wu D, Yu D, et al. Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. Med Oncol 2015;32:391.
104. Weiss L, Hoffman GE, Schreiber R, Andrea H, Fuchs E, et al. Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biol Chem Hoppe-Seyler 1986;367:905-12.
105. Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2015;2:808-24.
106. Jin Q, Yuan LX, Boulbes D, Baek JM, Wang YN, et al. Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells. Breast Cancer Res 2010;12:R96.
107. Kumar-Sinha C, Ignatoski KW, Lippman ME, Ethier SP, Chinnaiyan AM. Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res 2007;63:132-9.
108. Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 2005;24:39-46.
109. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res 2004;64:2070-5.
110. Alwarawrah Y, Hughes P, Loiselle D, Carlson DA, Darr DB, et al. Fasnall, a selective FASN inhibitor, shows potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer. Cell Chem Biol 2016;23:678-88.
111. Zhi J, Melia AT, Funk C, Viger-Chougnet A, Hopfgartner G, et al. Metabolic profiles of minimally absorbed orlistat in obese/overweight volunteers. J Clin Pharmacol 1996;36:1006-11.
112. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000;288:2379-81.
113. Brenner AJ, Von Hoff DD, Infante JR, Patel MR, Jones SF, et al. First-in-human investigation of the oral first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640. J Clin Oncol 2015;33:TPS2615.
114. Yoon S, Lee MY, Park SW, Moon JS, Ko YK, et al. Up-regulation of acetyl-CoA carboxylase α and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem 2007;282:26122-31.
115. Wang D, Yin L, Wei J, Yang Z, Jiang G. ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumor Biol 2017;39:1010428317698338.
116. Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 2016;22:1108.
117. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 2005;8:311-21.
118. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 2005;24:6465.
119. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008;8:224-36.
120. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011;17:1498.
121. Balaban S, Shearer RF, Lee LS, van Geldermalsen M, Schreuder M, et al. Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab 2017;5:1.
122. Kuemmerle NB, Rysman E, Lombardo PS, Flanagan AJ, Lipe BC, et al. Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther 2011;10:427-36.
123. Goldberg IJ, Eckel RH, Abumrad NA. Regulation of fatty acid uptake into tissues: lipoprotein lipase-and CD36-mediated pathways. J Lipid Res 2009;50:S86-90.
124. Pascual G, Avgustinova A, Mejetta S, Martín M, Castellanos A, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 2017;541:41.
125. Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 2018;37:2285.
127. Liu Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis 2006;9:230.
128. Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 2016;22:427.
129. Giudetti AM, De Domenico S, Ragusa A, Lunetti P, Gaballo A, et al. A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program. Biochim Biophys Acta 2019;1864:344-57.
130. McDonnell E, Crown SB, Fox DB, Kitir B, Ilkayeva OR, et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Rep 2016;17:1463-72.
131. Corbet C, Pinto A, Martherus R, de Jesus JP, Polet F, et al. Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metab 2016;24:311-23.
132. Balaban S, Lee LS, Varney B, Aishah A, Gao Q, et al. Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis. Mol Oncol 2018;12:1623-38.
133. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 2010;140:49-61.
134. Jarc E, Kump A, Malavašič P, Eichmann TO, Zimmermann R, et al. Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress. Biochim Biophys Acta 2018;1863:247-65.
135. Bi J, Ichu TA, Zanca C, Yang H, Zhang W, et al. Oncogene amplification in growth factor signaling pathways renders cancers dependent on membrane lipid remodeling. Cell Metab 2019;30:525-38.
136. Dubianski R, Sarnowska E, Leszczynski M, Kubala S, Olszewski W, et al. 17P HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch. Ann of Oncol 2018;29.
137. Hultsch S, Kankainen M, Paavolainen L, Kovanen RM, Ikonen E, et al. Association of tamoxifen resistance and lipid reprogramming in breast cancer. BMC Cancer 2018;18:850.
138. Du T, Sikora MJ, Levine KM, Tasdemir N, Riggins RB, et al. Key regulators of lipid metabolism drive endocrine resistance in invasive lobular breast cancer. Breast Cancer Res 2018;20:106.
139. Jin J, Valanejad L, Nguyen TP, Lewis K, Wright M, et al. Activation of CDK4 triggers development of non-alcoholic fatty liver disease. Cell Rep 2016;16:744-56.
140. Kitajima S, Yoshida A, Kohno S, Li F, Suzuki S, et al. The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. Oncogene 2017;36:5145.
141. Tarrado-Castellarnau M, de Atauri P, Tarragó-Celada J, Perarnau J, Yuneva M, et al. De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition. Mol Syst Biol 2017;13.
143. Vazquez-Martin A, Colomer R, Brunet J, Menendez JA. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int J Oncol 2007;31:769-76.
144. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 2010;120:142-56.
145. Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev 2011;25:1041-51.
146. Li J, Zhao S, Zhou X, Zhang T, Zhao L, et al. Inhibition of lipolysis by mercaptoacetate and etomoxir specifically sensitize drug-resistant lung adenocarcinoma cell to paclitaxel. PLoS One 2013;8:e74623.
147. Wu X, Li Y, Wang J, Wen X, Marcus MT, et al. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS One 2013;8:e77060.
148. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37:217-22.
149. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005;15:702-13.
150. Nardella C, Chen Z, Salmena L, Carracedo A, Alimonti A, et al. Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev 2008;22:2172-7.
151. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316.
152. Chen Y, Qian J, He Q, Zhao H, Toral-Barza L, et al. mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget 2016;7:25224.
153. Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 2017;32:807-23.
154. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90.
155. Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 2012;32:2-11.
156. Hindupur SK, González A, Hall MN. The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 2015;7:a019141.
157. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13:251.
158. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-26.
159. Hsieh FS, Chen YL, Hung MH, Chu PY, Tsai MH, et al. Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK 4/6-independent manner. Mol Oncol 2017;11:1035-49.
