The Role of Akt Signalling Pathway in Neurological and Cardiovascular Pathologies

Year 2023, Volume: 82 Issue: 1, 95 - 108, 26.06.2023

Akshat Modi , Aahmad Mahoon Dharmeshkumar Modi

https://doi.org/10.26650/EurJBiol.2023.1240220

Abstract

The PI3K/Akt/mTOR signalling pathway plays a crucial role in several biological processes, including cell proliferation, survival, and apoptosis, as well as regulates numerous signalling pathways, including JNK, NF-𝜅B, and ERK pathways. The recent proliferation of signal transduction studies in neurological and cardiovascular diseases/injuries sheds light on Akt-dependent pathogenesis. The downregulation of the Akt signalling pathway 24 hours post-injury prevents neurogenesis and promotes the progression of severe secondary injuries, including neuroinflammation, scar formation, and neuronal and glial necrosis, following traumatic brain and spinal cord injury, suggesting designing therapeutic approaches within a 24-hour window postinjury. Similarly, the downregulation of the Akt signalling pathway in myocardial infarction lowers cardiovascular protection, limits neurovascularization, and inhibits cell survival. Following myocarditis, the Akt signalling network is upregulated, leading to aggravated inflammation, and increased myocardial damage. Also, the upregulation of the PI3K/Akt/mTOR pathway in chordoma promotes tumor progression and invasion, leading to neuronal damage and impaired physiological functions. Future therapeutics that target the aberrant expression of key players in the PI3K/Akt/mTOR signalling pathway present a promising approach to treating several neurological and cardiovascular pathologies. This narrative review discusses the role of PI3K/Akt/mTOR signalling pathway in traumatic central nervous system injuries (brain and spinal cord), cardiac injury (myocardial infarction), inflammatory disease (myocarditis), and rare neurological cancer (chordoma) along with therapeutic targets that are known to prevent worsened outcomes and promote recovery following those conditions.

Keywords

PI3K/Akt/mTOR Signalling Pathway, Traumatic Spinal Cord Injury, Traumatic Brain Injury, Myocardial Infarction, Myocarditis, Chordoma.

References

• 1. Wang Z, Cui X, Hao G, He J. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma. Open Life Sci. 2021;16(1):1037-1044. google scholar
• 2. Xie Y, Shi X, Sheng K, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 2019;19(2):783-791. google scholar
• 3. Staal SP, Hartley JW. Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med. 1988;167(3):1259-1264. google scholar
• 4. Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol. 2005;17(2):150-157. google scholar
• 5. Zhang Z, Yao L, Yang J, Wang Z, Du G. PI3K/Akt and HIF 1 signaling pathway in hypoxia ischemia (Review). Mol Med Rep. 2018;18(4):3547-3554. google scholar
• 6. Linnerth-Petrik NM, Santry LA, Moorehead R, Jücker M, Woot-ton SK, Petrik J. Akt isoform specific effects in ovarian cancer progression. Oncotarget. 2016;7(46):74820-74833. google scholar
• 7. Zhang F, Ding T, Yu L, Zhong Y, Dai H, Yan M. Dexmedetomi-dine protects against oxygen-glucose deprivation-induced injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells. J Pharm Pharmacol. 2012;64(1):120-127. google scholar
• 8. Ciuffreda L, Falcone I, Incani UC, et al. PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting. Adv Biol Regul. 2014;56:66-80. google scholar
• 9. Ojeda L, Gao J, Hooten KG, et al. Critical role of PI3K/Akt/GSK3fi in motoneuron specification from human neural stem cells in response to FGF2 and EGF. PLoS One. 2011;6(8):e23414. doi: 10.1371/journal.pone.0023414. google scholar
• 10. Wyatt LA, Filbin MT, Keirstead HS. PTEN inhibition enhances neurite outgrowth in human embryonic stem cell-derived neu-ronal progenitor cells. J Comp Neurol. 2014;522(12):2741-2755. google scholar
• 11. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem. 1998;67:481-507. google scholar
• 12. Zhao S, Fu J, Liu F, Rastogi R, Zhang J, Zhao Y. Small in-terfering RNA directed against CTMP reduces acute traumatic brain injury in a mouse model by activating Akt. Neurol Res. 2014;36(5):483-490. google scholar
• 13. Rana A, Singh S, Sharma R, Kumar A. Traumatic brain in-jury altered normal brain signaling pathways: Implications for novel therapeutics approaches. Curr Neuropharmacol. 2019;17(7):614-629. google scholar
• 14. Marklund N. Rodent Models of Traumatic Brain Injury: Meth-ods and Challenges. In: Kobeissy FH, Dixon CE, Hayes RL, Mondello S, eds. Injury Models of the Central Nervous System. Vol 1462. Methods in Molecular Biology. Springer New York; 2016:29-46. google scholar
• 15. Bryan-Hancock C, Harrison J. The global burden of traumatic brain injury: preliminary results from the Global Burden of Disease Project. Injury Prevention. 2010;16:A17.http://dx.doi.org/10.1136/ip.2010.029215.61 google scholar
• 16. Chen CC, Hung TH, Lee CY, et al. Berberine protects against neuronal damage via suppression of glia-mediated inflamma-tion in traumatic brain injury. PLoS One. 2014;9(12):e115694. doi:10.1371/journal.pone.0115694. google scholar
• 17. Lagraoui M, Sukumar G, Latoche JR, Maynard SK, Dalgard CL, Schaefer BC. Salsalate treatment following traumatic brain injury reduces inflammation and promotes a neuroprotective and neurogenic transcriptional response with concomitant functional recovery. Brain Behav Immun. 2017;61:96-109. google scholar
• 18. Nikolaeva I. Targeting the PI3K/Akt/mTOR pathway in trau-matic brain injury and developmental disease (Thesis). 2016. google scholar
• 19. Noshita N, Lewen A, Sugawara T, Chan PH. Evidence of phos-phorylation of Akt and neuronal survival after transient fo-cal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2001;21(12):1442-1450. google scholar
• 20. Park J, Zhang J, Qiu J, et al. Combination therapy targeting Akt and mammalian target of rapamycin improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab. 2012;32(2):330-340. google scholar
• 21. Zhao S, Fu J, Liu X, Wang T, Zhang J, Zhao Y. Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats. Neurological Research. 2012;34(4):400-407. google scholar
• 22. Wang G, Jiang X, Pu H, et al. Scriptaid, a novel histone deacety-lase inhibitor, protects against traumatic brain injury via mod-ulation of PTEN and AKT pathway : scriptaid protects against TBI via AKT. Neurotherapeutics. 2013;10(1):124-142. google scholar
• 23. Yu N, Hu S, Hao Z. Benificial effect of stachydrine on the trau-matic brain injury induced neurodegeneration by attenuating the expressions of Akt/mTOR/PI3K and TLR4/NFk-B pathway. Transl Neurosci. 2018;9:175-182. google scholar
• 24. Zhang C, Zhu J, Zhang J, et al. Neuroprotective and anti-apoptotic effects of valproic acid on adult rat cerebral cortex through ERK and Akt signaling pathway at acute phase of trau-matic brain injury. Brain Research. 2014;1555:1-9. google scholar
• 25. Rozas NS, Redell JB, Hill JL, et al. Genetic activation of mTORC1 signaling worsens neurocognitive outcome after trau-matic brain injury. J Neurotrauma. 2015;32(2):149-158. google scholar
• 26. Guo D, Zeng L, Brody DL, Wong M. Rapamycin attenu-ates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS ONE. 2013;8(5):e64078. doi:10.1371/journal.pone.0064078. google scholar
• 27. Zhao L, Wu D, Sang M, Xu Y, Liu Z, Wu Q. Stachydrine ame-liorates isoproterenol-induced cardiac hypertrophy and fibrosis by suppressing inflammation and oxidative stress through in-hibiting NF-kB and JAK/STAT signaling pathways in rats. Int Immunopharmacol. 2017;48:102-109. google scholar
• 28. He H, Liu W, Zhou Y, et al. Sevoflurane post-conditioning atten-uates traumatic brain injury-induced neuronal apoptosis by pro-moting autophagy via the PI3K/AKT signaling pathway. DDDT. 2018;12:629-638. google scholar
• 29. Gao Y, Li J, Wu L, et al. Tetrahydrocurcumin provides neuro-protection in rats after traumatic brain injury: autophagy and the PI3K/AKT pathways as a potential mechanism. J Surg Res. 2016;206(1):67-76. google scholar
• 30. Miao J, Wang L, Zhang X, et al. Protective effect of aliskiren in experimental ischemic stroke: Up-regulated p-PI3K, p-AKT, Bcl-2 expression, attenuated Bax expression. Neurochem Res. 2016;41(9):2300-2310. google scholar
• 31. Zhang L, Ding K, Wang H, Wu Y, Xu J. Traumatic brain injury-induced neuronal apoptosis is reduced through modulation of PI3K and autophagy pathways in mouse by FTY720. Cell Mol Neurobiol. 2016;36(1):131-142. google scholar
• 32. Wang ZG, Cheng Y, Yu XC, et al. bFGF protects against blood-brain barrier damage through junction protein regulation via PI3K-Akt-Rac1 pathway following traumatic brain injury. Mol Neurobiol. 2016;53(10):7298-7311. google scholar
• 33. Wang C, Hu Z, Zou Y, et al. The post-therapeutic effect of rapamycin in mild traumatic brain-injured rats ensuing in the upregulation of autophagy and mitophagy. Cell Biol Int. 2017;41(9):1039-1047. google scholar
• 34. Sun J, Nan G. The extracellular signal-regulated kinase 1/2 path-way in neurological diseases: A potential therapeutic target (Re-view). Int J Mol Med. 2017;39(6):1338-1346. google scholar
• 35. Zhang P, Zhang L, Zhu L, et al. The change tendency of PI3K/Akt pathway after spinal cord injury. Am J Transl Res. 2015;7(11):2223-2232. google scholar
• 36. Yu WR, Fehlings MG. Fas/FasL-mediated apoptosis and inflam-mation are key features of acute human spinal cord injury: impli-cations for translational, clinical application. Acta Neuropathol. 2011;122(6):747-761. google scholar
• 37. Saxena T, Loomis KH, Pai SB, et al. Nanocarrier-mediated inhibition of macrophage migration inhibitory factor atten-uates secondary injury after spinal cord injury. ACS Nano. 2015;9(2):1492-1505. google scholar
• 38. Calvo M, Zhu N, Grist J, Ma Z, Loeb JA, Bennett DLH. Fol-lowing nerve injury neuregulin-1 drives microglial prolifera-tion and neuropathic pain via the MEK/ERK pathway. Glia. 2011;59(4):554-568. google scholar
• 39. Renfu Q, Rongliang C, Mengxuan D, et al. Anti-apoptotic signal transduction mechanism of electroacupuncture in acute spinal cord injury. Acupunct Med. 2014;32(6):463-471. google scholar
• 40. Zhang L, Gu S, Zhao C, Wen T. Combined treatment of neurotrophin-3 gene and neural stem cells is propitious to functional recovery after spinal cord injury. Cell Transplant. 2007;16(5):475-481. google scholar
• 41. Peviani M, Tortarolo M, Battaglia E, Piva R, Bendotti C. Specific induction of Akt3 in spinal cord motor neurons is neuroprotec-tive in a mouse model of familial amyotrophic lateral sclerosis. Mol Neurobiol. 2014;49(1):136-148. google scholar
• 42. Zhao R, Wu X, Bi XY, Yang H, Zhang Q. Baicalin at-tenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury. Neural Regen Res. 2022;17(5):1080-1087. google scholar
• 43. Wang X, Jiang C, Zhang Y, et al. The promoting effects of activated olfactory ensheathing cells on angiogenesis after spinal cord injury through the PI3K/Akt pathway. Cell Biosci. 2022;12(1):23. doi:10.1186/s13578-022-00765-y. google scholar
• 44. Zheng Z, Zeng Y, Zhu X, et al. ApoM-S1P modulates Ox-LDL-induced inflammation through the PI3K/Akt signaling pathway in HUVECs. Inflammation. 2019;42(2):606-617. google scholar
• 45. Zhu GS, Tang LY, Lv DL, Jiang M.Total flavones of abel-moschus manihot exhibits pro-angiogenic activity by activat-ing the VEGF-A/VEGFR2-PI3K/Akt signaling Axis. Am J Chin Med. 2018;46(3):567-583. google scholar
• 46. Zhang X, Zhao F, Zhao JF, Fu HY, Huang XJ, Lv BD. PDGF-mediated PI3K/AKT/3-catenin signaling regulates gap junc-tions in corpus cavernosum smooth muscle cells. Exp Cell Res. 2018;362(2):252-259. google scholar
• 47. Choi AR, Jeong MH, Hong YJ, et al. Clinical characteristics and outcomes in acute myocardial infarction patients with versus without any cardiovascular risk factors. Korean J Intern Med. 2019;34(5):1040-1049. google scholar
• 48. Golforoush P, Yellon DM, Davidson SM. Mouse models of atherosclerosis and their suitability for the study of my-ocardial infarction. Basic Res Cardiol. 2020;115(6):73. doi: 10.1007/s00395-020-00829-5. google scholar
• 49. Sabatine MS, Braunwald E. Thrombolysis in myocardial infarc-tion (TIMI) study group: JACC focus seminar 2/8. J Am Coll Cardiol. 2021;77(22):2822-2845. google scholar
• 50. Zhang Q, Wang L, Wang S, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7(1):78. doi:10.1038/s41392-022-00925-z. google scholar
• 51. Feng L, Li B, Xi Y, Cai M, Tian Z. Aerobic exercise and re-sistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction. Am J Physiol Cell Physiol. 2022;322(2):C164-C176. google scholar
• 52. Hua H, Zhang H, Chen J, Wang J, Liu J, Jiang Y. Targeting Akt in cancer for precision therapy. J Hematol Oncol. 2021;14(1):128. doi:10.1186/s13045-021-01137-8. google scholar
• 53. Eisenreich A, Rauch U. PI3K inhibitors in cardiovascular dis-ease. Cardiovasc Ther. 2011;29(1):29-36. google scholar
• 54. Mo XG, Chen QW, Li XS, et al. Suppression of NHE1 by small interfering RNA inhibits HIF-1a-induced angiogenesis in vitro via modulation of calpain activity. Microvasc Res. 2011;81(2):160-168 google scholar
• 55. Gao W, Chang G, Wang J, et al. Inhibition of K562 leukemia an-giogenesis and growth by selective Na+/H+ exchanger inhibitor cariporide through down-regulation of pro-angiogenesis factor VEGF. Leuk Res. 2011;35(11):1506-1511. google scholar
• 56. Liang X, Ding Y, Lin F, et al. Overexpression of ERBB4 re-juvenates aged mesenchymal stem cells and enhances angio-genesis via PI3K/AKT and MAPK/ERK pathways. FASEB J. 2019;33(3):4559-4570. google scholar
• 57. Fan J, Xu W, Nan S, Chang M, Zhang Y. MicroRNA-384-5p promotes endothelial progenitor cell proliferation and angio-genesis in cerebral ischemic stroke through the delta- likeli-gand 4-mediated Notch signaling pathway. Cerebrovasc Dis. 2020;49(1):39-54. google scholar
• 58. Du M, Shan J, Feng A, Schmull S, Gu J, Xue S. Oestrogen receptor fi activation potects against myocardial infarction via Notch1signalling. Cardiovasc Drugs Ther. 2020;34(2):165-178. google scholar
• 59. Huang H, Huang F, Huang JP. Transplantation of bone mar-row derived endothelial progenitor cells overexpressing Delta like 4 enhances functional neovascularization in ischemic my-ocardium. Mol Med Rep. 2013;8(5):1556-1562. google scholar
• 60. Zhou XL, Fang YH, Wan L, et al. Notch signaling inhibits cardiac fibroblast to myofibroblast transformation by antagonizing TGF-fi1/Smad3 signaling. J Cell Physiol. 2019;234(6):8834-8845. google scholar
• 61. Yao Q, Renault MA, Chapouly C, et al. Sonic hedgehog medi-ates a novel pathway of PDGF-BB-dependent vessel maturation. Blood. 2014;123(15):2429-2437. google scholar
• 62. Li M, Zheng H, Han Y, et al. LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regen-eration and repair after myocardial infarction. Theranostics. 2021;11(19):9397-9414. google scholar
• 63. Baraka SA, Tolba MF, Elsherbini DA, El-Naga RN, Awad AS, El-Demerdash E. Rosuvastatin and low-dose carvedilol combi-nation protects against isoprenaline-induced myocardial infarc-tion in rats: Role of PI3K/Akt/Nrf2/HO-1 signalling. Clin Exp Pharmacol Physiol. 2021;48(10):1358-1370. google scholar
• 64. Tan SH, Loo SJ, Gao Y, et al. Thymosin fi4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction. Theranostics. 2021;11(16):7879-7895. google scholar
• 65. Luo W, Gong Y, Qiu F, et al. NGF nanoparticles enhance the po-tency of transplanted human umbilical cord mesenchymal stem cells for myocardial repair. Am J Physiol Heart Circ Physiol. 2021;320(5):H1959-H1974. google scholar
• 66. Gnecchi M, He H, Noiseux N, et al. Evidence support-ing paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 2006;20(6):661-669. google scholar
• 67. Li X, Zhang H, An G, et al. S-Nitrosylation of Akt by organic nitrate delays revascularization and the recovery of cardiac func-tion in mice following myocardial infarction. J Cell Mol Med. 2021;25(1):27-36. google scholar
• 68. Li S, Wang Y, Zhao C, et al. Akt inhibitor deguelin aggravates inflammation and fibrosis in myocarditis. Iran J Basic Med Sci. 2019;22(11):1275-1282. google scholar
• 69. Zhang Q, Hu L qun, Li H qi, Wu J, Bian N na, Yan G. Beneficial effects of andrographolide in a rat model of autoimmune my-ocarditis and its effects on PI3K/Akt pathway. Korean J Physiol Pharmacol. 2019;23(2):103. google scholar
• 70. Liu HS, Zhang J, Guo JL, Lin CY, Wang ZW. Phosphoinosi-tide 3-kinase inhibitor LY294002 ameliorates the severity of myosin-induced myocarditis in mice. Curr Res Transl Med. 2016;64(1):21-27. google scholar
• 71. Song Y, Ge W, Cai H, Zhang H. Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-^B pathway. J Cardiovasc Pharmacol Ther. 2013;18(6):560-569. google scholar
• 72. Chen Z, Yang L, Liu Y, et al. LY294002 and Rapamycin pro-mote coxsackievirus-induced cytopathic effect and apoptosis via inhibition of PI3K/AKT/mTOR signaling pathway. Mol Cell Biochem. 2014;385(1-2):169-177. google scholar
• 73. Liu HS, Zhang J, Guo JL, Lin CY, Wang ZW. Phosphoinosi-tide 3-kinase inhibitor LY294002 ameliorates the severity of myosin-induced myocarditis in mice. Curr Res Transl Med. 2016;64(1):21-27. google scholar
• 74. Ouyang S, Zeng Q, Tang N, et al. Akt-1 and Akt-2 differen-tially regulate the development of experimental autoimmune en-cephalomyelitis by controlling proliferation of thymus-derived regulatory T cells. J Immunol. 2019;202(5):1441-1452. google scholar
• 75. Chang H, Li X, Cai Q, et al. The PI3K/Akt/mTOR pathway is involved in CVB3-induced autophagy of HeLa cells. Int J Mol Med. 2017;40(1):182-192. google scholar
• 76. Henao-Martmez AF, Agler AH, Watson AM, et al. AKT net-work of genes and impaired myocardial contractility during murine acute Chagasic myocarditis. Am J Trop Med Hyg. 2015;92(3):523-529. google scholar
• 77. Henao-Martmez AF, Parra-Henao G. Murine heart gene ex-pression during acute Chagasic myocarditis. Genom Data. 2015;4:76-77. google scholar
• 78. He H, Chang X, Gao J, Zhu L, Miao M, Yan T. Salidroside mitigates sepsis-induced myocarditis in rats by regulating IGF-1/PI3K/Akt/GSK-3p signaling. Inflammation. 2015;38(6):2178-2184. google scholar
• 79. Li Q, Li Y, Li J, et al. FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1a/CEACAM5 functional axis. Int J Biol Sci. 2018;14(7):726-735. google scholar
• 80. Hussain I, Waheed S, Ahmad KA, Pirog JE, Syed V. Scutel-laria baicalensis targets the hypoxia-inducible factor-1a and enhances cisplatin efficacy in ovarian cancer. J Cell Biochem. 2018;119(9):7515-7524. google scholar
• 81. Fu Q, Gao L, Fu X, Meng Q, Lu Z. Scutellaria baicalensis inhibits Coxsackievirus B3-induced myocarditis via AKT and p38 pathways. J Microbiol Biotechnol. 2019;29(8):1230-1239. doi:10.4014/jmb.1904.04050. google scholar
• 82. Chen HW, Lin AH, Chu HC, et al. Inhibition of TNF-a-induced inflammation by andrographolide via down-regulation of the PI3K/Akt signaling pathway. J Nat Prod. 2011;74(11):2408-2413. google scholar
• 83. Lu CY, Yang YC, Li CC, Liu KL, Lii CK, Chen HW. An-drographolide inhibits TNFa-induced ICAM-1 expression via suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression through the PI3K/Akt/Nrf2 and PI3K/Akt/AP-1 pathways in human endothelial cells. Biochem Pharmacol. 2014;91(1):40-50. google scholar
• 84. Shioi T. The conserved phosphoinositide 3-kinase pathway de-termines heart size in mice. EMBO J. 2000;19(11):2537-2548. google scholar
• 85. Shiojima I. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005;115(8):2108-2118. google scholar
• 86. Ulici V, Hart J. Chordoma. Arch Pathol Lab Med. 2022;146(3):386-395. google scholar
• 87. Williams BJ, Raper DMS, Godbout E, et al. Diagnosis and treat-ment of chordoma. J Natl Compr Canc Netw. 2013;11(6):726-731. google scholar
• 88. Rinner B, Weinhaeusel A, Lohberger B, et al. Chor-doma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. doi:10.1371/journal.pone.0056609. google scholar
• 89. Tamborini E, Virdis E, Negri T, et al. Analysis of receptor ty-rosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol. 2010;12(8):776-789. google scholar
• 90. Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res.2011;1(1):4. google scholar
• 91. Shalaby A, Presneau N, YeH, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011;223(3):336-346. google scholar
• 92. Choy E, MacConaill LE, Cote GM, et al. Genotyping cancer-associated genes in chordoma identifies mutations in onco-genes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 2014;9(7):e101283. doi:10.1371/journal.pone.0101283. google scholar
• 93. Tauziede-Espariat A, Bresson D, Polivka M, et al. Prognostic and therapeutic markers in Chordomas: A study of 287 tumors. J Neuropathol Exp Neurol. 2016;75(2):111-120. google scholar
• 94. Tarpey PS, Behjati S, Young MD, et al. The driver land-scape of sporadic chordoma. Nat Commun. 2017;8(1):890.doi: 10.1038/s41467-017-01026-0. google scholar
• 95. Meng T, Jin J, Jiang C, et al.Molecular targeted therapy in the treatment of Chordoma: A systematic review. Front Oncol. 2019;9:30. doi:10.3389/fonc.2019.00030. google scholar
• 96. de Castro CV, Guimaraes G, Aguiar S, et al. Tyrosine kinase re-ceptor expression in chordomas: phosphorylated AKT correlates inversely with outcome. Hum Pathol. 2013;44(9):1747-1755. google scholar
• 97. Wu Z, Wang L, Guo Z, et al. Experimental study on differences in clivus chordoma bone invasion: an iTRAQ-based quantitative proteomic analysis. PLoS One. 2015;10(3):e0119523.doi:10.1371/journal.pone.0119523. google scholar
• 98. Chen K, Mo J, Zhou M, et al. Expression of PTEN and mTOR in sacral chordoma and association with poor prognosis. Med Oncol. 2014;31(4):886.doi:10.1007/s12032-014-0886-7. google scholar
• 99. Scheipl S, Barnard M, Cottone L, et al. EGFR inhibitors identi-fied as a potential treatment for chordoma in a focused compound screen. J Pathol. 2016;239(3):320-334. google scholar
• 100. Alholle A, Brini AT, Bauer J, et al. Genome-wide DNA methy-lation profiling of recurrent and non-recurrent chordomas. Epi-genetics. 2015;10(3):213-220. google scholar
• 101. Otani R, Mukasa A, Shin M, et al. Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma. J Neurosurg. 2018;128(5):1428-1437. google scholar
• 102. Li G, Cai L, Zhou L. Microarray gene expression profiling and bioinformatics analysis reveal key differentially expressed genes in clival and sacral chordoma cell lines. Neurol Res. 2019;41(6):554-561. google scholar
• 103. Liang C, Ma Y, Yong L, et al. Y-box binding protein-1 pro-motes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma. Cancer Sci. 2019;110(1):166-179. google scholar
• 104. Ricci-Vitiani L, Runci D, D’Alessandris QG, et al. Chemother-apy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin. Neoplasia. 2013;15(7):773-782. google scholar
• 105. Wang K, Tian K, Wang L, et al. Brachyury: A sensitive marker, but not a prognostic factor, for skull base chordomas. Mol Med Rep. 2015;12(3):4298-4304. google scholar
• 106. Jahanafrooz Z, Stallinger A, Anders I, et al. Influence of silibinin and p-p -dimethylacrylshikonin on chordoma cells. Phytomedicine. 2018;49:32-40. google scholar
• 107. Lee DH, Zhang Y, Kassam AB, et al. Combined PDGFR and HDAC inhibition overcomes PTEN dis-ruption in Chordoma. PLoS One. 2015;10(8):e0134426. doi:10.1371/journal.pone.0134426. google scholar
• 108. Davies JM, Robinson AE, Cowdrey C, et al. Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma. J Neurosurg. 2014;120(2):331-336. google scholar
• 109. Burger A, Vasilyev A, Tomar R, et al. A zebrafish model of chor-doma initiated by notochord-driven expression of HRASV12. Dis Model Mech. 2014;7(7):907-913. google scholar
• 110. Lebellec L, Chauffert B, Blay JY, et al. Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sar-coma Group (GSF/GETO) and the Association des Neuro-Oncologues d’Expression Française (ANOCEF). EurJ Cancer. 2017;79:119-128. google scholar
• 111. Stacchiotti S, Morosi C, Lo Vullo S, et al. Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study. Cancer. 2018;124(20):4056-4063. google scholar
• 112. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-D1082. google scholar
• 113. Harding SD, Armstrong JF, Faccenda E, et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2022: curating pharmacology for COVID-19, malaria and antibacterials. Nucleic Acids Res. 2022;50(D1):D1282-D1294. google scholar