ANÁLISIS IN SILICO DE LA INTERACCIÓN ENTRE RIMEGEPANT Y HRAS COMO DIANA TERAPÉUTICA EN EL CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS

Fabricio Jácome Campos; Anthony Fernando  González

doi:10.47187/perf.v1i32.298

Autores/as

Fabricio Jácome Campos Investigador Independiente, Ambato, Ecuador
Anthony Fernando González Investigador Independiente, Ambato, Ecuador

DOI:

https://doi.org/10.47187/perf.v1i32.298

Palabras clave:

diana terapéutica, gen HRAS, Rimegepant, bioinformática, MAPK

Resumen

El cáncer de pulmón ocasiona 1.800.000 muertes a nivel mundial. Las neoplasias pulmonares se dividen en cáncer de pulmón de células no pequeñas y cáncer de pulmón de células pequeñas. El primero abarca el 80% de los casos y se subdivide en adenocarcinoma, carcinoma de células grandes y carcinoma de células escamosas. El objetivo de este estudio es analizar una posible diana molecular terapéutica en el cáncer de pulmón de células no pequeñas mediante un enfoque in silico. La metodología incluyó un análisis de expresión diferencial utilizando GEO2R, seguido de una comparación de genes con bases de datos como Malacards, Harmonizome y KEGG. Además, se construyeron redes de interacción mediante Cytoscape para identificar las interacciones entre los genes relacionados con el cáncer. Posteriormente, se empleó DrugBank para identificar una posible diana terapéutica y se reconoció el sitio drogable a través de DOGSiteScorer. Los resultados indican que el fármaco Rimegepant muestra propiedades farmacocinéticas y de toxicidad favorables, lo que sugiere que podría ser una alternativa viable para el desarrollo de medicamentos dirigidos a la proteína HRAS. Este hallazgo abre nuevas perspectivas para el tratamiento del cáncer de pulmón de células no pequeñas, mejorando su abordaje terapéutico.

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Citas

Fois SS, Paliogiannis P, Zinellu A, Fois AG, Cossu A, Palmieri G. Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer. Int J Mol Sci. 2021;22(2):1–19. doi: 10.3390/IJMS22020612

Zavala-Hoppe AN, Recalde-Chávez JZ, Saldarriaga-García AJ, Quiroz-Villafuerte WA. Epidemiología y factores de riesgo asociados al cáncer de pulmón en los países de Latinoamérica y Europa. MQRInvestigar. 2024;8(1):1483–99.

Duma N, Santana-Davila R, Molina JR. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc. 2019;94(8):1623–40. doi: 10.1016/J.MAYOCP.2019.01.013

Rivas S, Armisén R. El cáncer de pulmón de células no pequeñas en la era de la medicina de precisión. Rev Médica Clínica Las Condes. 2022;33(1):25–35. doi: 10.1016/J.RMCLC.2022.01.001

Saab S, Zalzale H, Rahal Z, Khalifeh Y, Sinjab A, Kadara H. Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment. Front Immunol. 2020;11. doi: 10.3389/FIMMU.2020.00159

Wang Y, Zou S, Zhao Z, Liu P, Ke C, Xu S. New insights into small-cell lung cancer development and therapy. Cell Biol Int. 2020;44(8):1564–76. doi: 10.1002/CBIN.11359

Hoy H, Lynch T, Beck M. Surgical Treatment of Lung Cancer. Crit Care Nurs Clin North Am. 2019;31(3):303–13. doi: 10.1016/J.CNC.2019.05.002

Hsu PC, Jablons DM, Yang CT, You L. Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC). Int J Mol Sci. 2019;20(15). doi: 10.3390/IJMS20153821

Alexander M, Kim SY, Cheng H. Update 2020: Management of Non-Small Cell Lung Cancer. Lung. 2020;198(6):897–907. doi: 10.1007/S00408-020-00407-5

Escobar P, Mercedes M, Rodríguez G, Emilio M, Moredo A, Escobar EP. Cáncer de pulmón de células no pequeñas : presentación de caso. Arch Médico Camaguey. 2017;21(2):1–6.

Lin L, Ding D, Xiao X, Li B, Cao P, Li S. Trametinib potentiates TRAIL-induced apoptosis via FBW7-dependent Mcl-1 degradation in colorectal cancer cells. J Cell Mol Med. 2020;24(12):6822–32. doi: 10.1111/JCMM.15336

Rivera C, Granados A, Ramírez J. Erlotinib vs. Gefitinib en cáncer de pulmón de células no pequeñas avanzado o metastásico: Una comparación indirecta de eficacia. Gac Mex Oncol. 2010;9(5):1–9.

Campos-Parra AD, Cruz-Rico G, Arrieta O. Genotipificación en cáncer de pulmón de células no pequeñas. Gac Mex Oncol. 2012;11(1):35–44.

Auxiliadora Castillo-Muñoz M, Abdel-Kader-Martín L, Beltrán-Calvo C, Isabel-Gómez R, Romero-Tabares A, Molina-López T. Erlotinib y gefitinib en primera línea de cáncer de pulmón no microcítico en estadio avanzado o metastásico, con mutación activadora del EGFR.

Liu J, Zhang X, Cao X. Dendritic cells in systemic lupus erythematosus: From pathogenesis to therapeutic applications. J Autoimmun. 2022;132. doi: 10.1016/J.JAUT.2022.102856

Dalal N, Jalandra R, Sharma M, Prakash H, Makharia GK, Solanki PR, et al. Omics technologies for improved diagnosis and treatment of colorectal cancer: Technical advancement and major perspectives. Biomed Pharmacother. 2020;131:110648.

Gore S, Sanz García E, Hendrickx PMS, Gutmanas A, Westbrook JD, Yang H, et al. Validation of Structures in the Protein Data Bank. Structure. 2017;25(12):1916–27. doi: 10.1016/J.STR.2017.10.009

Evans C, Hardin J, Stoebel DM. Selecting between-sample RNA-Seq normalization methods from the perspective of their assumptions. Brief Bioinform. 2018;19(5):776–92. doi: 10.1093/BIB/BBX008

Boyero Corral L. Análisis de los perfiles de expresión génica en cáncer de pulmón: Valor pronóstico en pacientes con cáncer de pulmón no microcítico sometidos a toracotomía. Universidad de Granada. 2016.

Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, et al. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012;22(7):1197–211. doi: 10.1101/GR.132662.111

Kareff SA, Trabolsi A, Krause HB, Samec T, Elliott A, Rodriguez E, et al. The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors. Cancers (Basel). 2024;16(8). doi: 10.3390/CANCERS16081572

Stephen AG, Esposito D, Bagni RG, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25(3):272–81. doi: 10.1016/J.CCR.2014.02.017

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–74. doi: 10.1038/NRC3106

Degirmenci U, Wang M, Hu J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells. 2020;9(1). doi: 10.3390/CELLS9010198

Tomasini P, Walia P, Labbe C, Jao K, Leighl NB. Targeting the KRAS Pathway in Non-Small Cell Lung Cancer. Oncologist. 2016;21(12):1450. doi: 10.1634/THEONCOLOGIST.2015-0084

Gómez-López A, Revuelta-Salgado F, García-Luján R. Cáncer de pulmón de células no pequeñas. Med - Programa Form Médica Contin Acreditado. 2022;13(67):3933–41.

Purba ER, Saita EI, Maruyama IN. Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The “Rotation Model”. Cells. 2017;6(2). doi: 10.3390/CELLS6020013

Figarol S, Delahaye C, Gence R, Doussine A, Cerapio JP, Brachais M, et al. Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies. Nat Commun. 2024;15(1):5345. doi: 10.1038/S41467-024-49360-4

Koch S, Claesson-Welsh L. Signal Transduction by Vascular Endothelial Growth Factor Receptors. Cold Spring Harb Perspect Med. 2012;2(7). doi: 10.1101/CSHPERSPECT.A006502

Cseh B, Doma E, Baccarini M. “RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway. Febs Lett. 2014;588(15):2398. doi: 10.1016/J.FEBSLET.2014.06.025

Veluswamy R, Mack PC, Houldsworth J, Elkhouly E, Hirsch FR. KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing. J Mol Diagn. 2021;23(5):507–20. doi: 10.1016/J.JMOLDX.2021.02.002

Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev. 2020;89. doi: 10.1016/J.CTRV.2020.102070

Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac cancer. 2018;9(4):423–30. doi: 10.1111/1759-7714.12613

Fan Z, Zhang L, Zhang S, Liu A, Li S, Cao X, et al. Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib. Reports Biochem Mol Biol. 2023;12(1):74–82. doi: 10.52547/RBMB.12.1.74

Volkamer A, Kuhn D, Rippmann F, Rarey M. DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics. 2012;28(15):2074–5. doi: 10.1093/BIOINFORMATICS/BTS310

Fährrolfes R, Bietz S, Flachsenberg F, Meyder A, Nittinger E, Otto T, et al. ProteinsPlus: a web portal for structure analysis of macromolecules. Nucleic Acids Res. 2017;45(W1):W337–43. doi: 10.1093/NAR/GKX333

Michel M, Visnes T, Homan EJ, Seashore-Ludlow B, Hedenström M, Wiita E, et al. Computational and Experimental Druggability Assessment of Human DNA Glycosylases. ACS Omega. 2019;4(7):11642–56. doi: 10.1021/ACSOMEGA.9B00162/SUPPL_FILE/AO9B00162_SI_002.XLSX

Fitri A, Basultan H, Iryani. Hydrophobic Pocket of SARS-Cov-2 Spike Glycoprotein are Potential as Binding Pocket. J Phys Conf Ser. 2021;1788(1). doi: 10.1088/1742-6596/1788/1/012021

Salem MM, Gerges MN, Noser AA. Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells. Sci Reports 2022 121. 2022;12(1):1–20. doi: 10.1038/s41598-022-26571-7

Li J, Ma X, Guo S, Hou C, Shi L, Zhang H, et al. A Hydrophobic‐Interaction‐Based Mechanism Triggers Docking between the SARS‐CoV‐2 Spike and Angiotensin‐Converting Enzyme 2. Glob Challenges. 2020;4(12). doi: 10.1002/GCH2.202000067

Varma AK, Patil R, Das S, Stanley A, Yadav L, Sudhakar A. Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of Drug-Designing. PLoS One. 2010;5(8).

Mustafai A, Zubair M, Hussain A, Ullah A. Recent Progress in Proteins-Based Micelles as Drug Delivery Carriers. Polymers (Basel). 2023;15(4). doi: 10.3390/POLYM15040836

Dunga AK, Allaka TR, Kethavarapu Y, Nechipadappu SK, Pothana P, Kuppan C, et al. Design, Synthesis, Molecular Docking, ADMET, and Biological Studies of Some Novel 1,2,3-Triazole Linked Tetrazoles as Anticancer Agents. Curr Org Synth. 2022;20(5):576–87.

Infield DT, Rasouli A, Galles GD, Chipot C, Tajkhorshid E, Ahern CA. Cation-π interactions and their functional roles in membrane proteins. J Mol Biol. 2021;433(17):167035. doi: 10.1016/J.JMB.2021.167035

Vernon RMC, Chong PA, Tsang B, Kim TH, Bah A, Farber P, et al. Pi-Pi contacts are an overlooked protein feature relevant to phase separation. Elife. 2018;7. doi: 10.7554/ELIFE.31486

Hubbard RE, Kamran Haider M. Hydrogen Bonds in Proteins: Role and Strength. Encycl Life Sci. 2010; doi: 10.1002/9780470015902.A0003011.PUB2

Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv. 2016;2(3). doi: 10.1126/SCIADV.1501240

Newberry RW, Raines RT. The n→π∗ Interaction. Acc Chem Res. 2017;50(8):1838–46. doi: 10.1021/ACS.ACCOUNTS.7B00121/ASSET/IMAGES/LARGE/AR-2017-001218_0009.JPEG

Pratama MRF, Poerwono H, Siswodiharjo S. ADMET properties of novel 5-O-benzoylpinostrobin derivatives. J Basic Clin Physiol Pharmacol. 2019;30(6). doi: 10.1515/JBCPP-2019-0251

Flores-Holguín N, Frau J, Glossman-Mitnik D. In Silico Pharmacokinetics, ADMET Study and Conceptual DFT Analysis of Two Plant Cyclopeptides Isolated From Rosaceae as a Computational Peptidology Approach. Front Chem. 2021;9:708364.

Pham-The H, Cabrera-Pérez MÁ, Nam NH, Castillo-Garit JA, Rasulev B, Le-Thi-Thu H, et al. In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling. Curr Top Med Chem. 2018;18(26):2209–29.

Youhanna S, Lauschke VM. The Past, Present and Future of Intestinal In Vitro Cell Systems for Drug Absorption Studies. J Pharm Sci. 2021;110(1):50–65. doi: 10.1016/J.XPHS.2020.07.001

Robinson K, Tiriveedhi V. Perplexing Role of P-Glycoprotein in Tumor Microenvironment. Front Oncol. 2020;10. doi: 10.3389/FONC.2020.00265

Cox D. How not to discover a drug - integrins. Expert Opin Drug Discov. 2021;16(2):197–211. doi: 10.1080/17460441.2020.1819234

Fatima S, Gupta P, Sharma S, Sharma A, Agarwal SM. ADMET profiling of geographically diverse phytochemical using chemoinformatic tools. Future Med Chem. 2020;12(1):69–87. doi: 10.4155/FMC-2019-0206

Takomthong P, Waiwut P, Yenjai C, Sombatsri A, Reubroycharoen P, Lei L, et al. Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties. Pharmaceuticals (Basel). 2021;14(9). doi: 10.3390/PH14090888

Sevrioukova IF, Poulos TL. Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems. Dalton Trans. 2013;42(9):3116–26. doi: 10.1039/C2DT31833D