Proposal of combined therapeutic strategies for KRAS in non-small cell lung cancer based on an in silico analysis
DOI:
https://doi.org/10.24265/horizmed.2024.v24n2.07Keywords:
Carcinoma, Non-Small-Cell Lung , Anaplastic Lymphoma Kinase , Molecular Docking SimulationAbstract
Objective: Patients with non-small cell lung cancer positive for the anaplastic lymphoma kinase (ALK+) gene mutation who also have mutations in the Kirsten rat sarcoma (KRAS) gene, such as KRAS G12C, are showing resistance to both anaplastic lymphoma kinase (ALK) gene and KRAS inhibitors. Therefore, the interaction between ALK inhibitors and KRAS was analyzed to suggest a synergy between them. Materials and methods: The study performed homology modeling of the KRASwt, KRAS G12C and ALKwt structures. Subsequently, molecular dockings were carried out to determine the binding energy of ALK and KRAS inhibitors and to evaluate the possible interaction of ALK inhibitors with KRAS and the KRAS G12C structure. Finally, the expression in the RAS/MEK pathway was analyzed using the Western Blot technique. Results: The binding energy values show the potential interaction of ALKwt inhibitors, such as crizotinib and alectinib, with the KRASwt and KRAS G12C structures. The binding of crizotinib to KRASwt and KRAS G12C, respectively, indicates interaction energy values (42.77 kcal/mol and 46.20 kcal/mol) which are very similar to those obtained between crizotinib and ALK (42.37 kcal/mol). In turn, alectinib bound to the same site as drugs targeting KRAS and KRAS G12C, and showed interaction energy values (51.74 kcal/mol and 54.69 kcal/mol, respectively) higher than those obtained with ALK (44.94 kcal/mol). Finally, a significant decrease in RAS expression within the RAS/MEK pathway was observed in ALK+ and ALK 1196M lung cancer cell lines treated with crizotinib and alectinib. Conclusions: In silico techniques of this study demonstrate the potential binding of ALK inhibitors (crizotinib and alectinib) to the KRAS structure. In addition, this allows suggesting a possible combined therapy between KRAS and ALK inhibitors for cases of coexistence of both mutations that can be assessed in subsequent trials with cell lines.
Downloads
References
Amorín Kajatt E. Lung cancer: a review of current knowledge, diagnostic methods and therapeutic perspectives. Rev Peru Med Exp Salud Publica [Internet]. 2013;30(1):85-92.
Dammacco F, Silvestris F. Oncogenomics. 1.ª ed. India: Academic press; 2018.
Sabir SR, Yeoh S, Jackson G, Bayliss R. EML4-ALK variants: biological and molecular properties, and the implications for patients. Cancers (Basel) [Internet]. 2017;9(9):118.
Liu XQ, Kiefl R, Roskopf C, Tian F, Huber RM. Interactions among lung cancer cells, fibroblasts, and macrophages in 3D co-cultures and the impact on MMP-1 and VEGF expression. PLoS One [Internet]. 2016;11(5):1–14. 5.
Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-smallh cell lung cancer (NSCLC). Thorac Cancer [Internet]. 2018;9(4):423–30.
Muller IB, De Langen AJ, Honeywell RJ, Giovannetti E, Peters GJ. Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib. Expert Rev Anticancer Ther [Internet]. 2016;16(2):147–57.
Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther [Internet]. 2021;6(1):1–20.
Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: past, present and future. Int J Mol Sci [Internet]. 2020;21(12):1–30.
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 [Internet]. 2021;23(5):507–20.
Román M, Baraibar I, López I, Nadal E, Rolfo C, Vicent S, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer [Internet]. 2018;17(1):1–14.
Lee A. Sotorasib: A review in KRAS G12C mutation-positive non-small cell lung cancer. Target Oncol [Internet]. 2022;17(6):727–33.
Elliott J, Bai Z, Hsieh SC, Kelly SE, Chen L, Skidmore B, et al. ALK inhibitors for non-small cell lung cancer: a systematic review and network meta-analysis. PLoS One [Internet]. 2020;15(2):1–18.
Sankar K, Gadgeel SM, Qin A. Molecular therapeutic targets in non-small cell lung cancer. Expert Rev Anticancer Ther [Internet]. 2020;20(8):647–61.
Pan Y, Deng C, Qiu Z, Cao C, Wu F. The resistance mechanisms and treatment strategies for ALK-Rearranged non-small cell lung cancer. Front Oncol [Internet]. 2021;11:713530.
Friboulet Luc, Li N, Katayama R, Lee CC, Gairnor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in nonsmall cell lung cancer. Cancer Discov [Internet]. 2014;4(6):662–73.
Bayliss R, Choi J, Fennell DA, Fry AM, Richards MW. Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs. Cell Mol Life Sci [Internet]. 2016;73(6):1209–24.
Rao Q, Zuo B, Lu Z, Gao X, You A, Wu C, et al. Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology [Internet]. 2016;64(2):456–72.
Bordi P, Tiseo M, Rofi E, Petrini I, Restante G, Danesi R, et al. Detection of ALK and KRAS mutations in circulating tumor DNA of patients with advanced ALK-Positive NSCLC with disease progression during crizotinib treatment. Clin Lung Cancer [Internet]. 2017;18(6):692–7.
Martorell PM, Huerta M, Compañ Quilis A, Abellán R, Seda E, Blesa S, et al. Coexistence of EGFR, KRAS, BRAF, and PIK3CA mutations and ALK rearrangement in a comprehensive cohort of 326 consecutive Spanish nonsquamous NSCLC patients. Clin Lung Cancer [Internet]. 2017;18(6):e395–402.
Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep Med [Internet]. 2021;2(1):100186.
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules [Internet]. 2015;20(7):13384–421.
Fontana D, Ceccon M, Gambacorti-Passerini C, Mologni L. Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK. Cancer Med [Internet]. 2015;4(7):953–65.
Lee B, Lee T, Lee SH, Choi YL, Han J. Clinicopathologic characteristics of EGFR, KRAS, and ALK alterations in 6,595 lung cancers. Oncotarget [Internet]. 2016;7(17):23874–84.
De Langen AJ, Johnson ML, Mazieres J, Dingemans Anne-Marie, Mountzios G, Pless M, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet [Internet]. 2023;401(10378):733–46.
Schmid S, Gautschi O, Rothschild S, Mark M, Froesch P, Klingbiel D, et al. Clinical outcome of ALK-Positive non–small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIs). J Thorac Oncol [Internet]. 2017;12(4):681–8.
Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired Resistance to KRAS G12C inhibition in cancer . N Engl J Med [Internet]. 2021;384(25):2382–93.
Yang SR, Schultheis AM, Yu H, Mandelker D, Ladanyi M, Büttner R. Precision medicine in non-small cell lung cancer: Current applications and future directions. Semin Cancer Biol [Internet]. 2022;84:184–98.
Adderley H, Blackhall FH, Lindsay CR. KRAS-mutant non-small cell lung cancer: converging small molecules and immune checkpoint inhibition. EBioMedicine [Internet]. 2019;41:711–6.
Suzuki S, Yonesaka K, Teramura T, Takehara T, Kato R, Sakai H, et al. KRAS inhibitor-resistance in MET-amplified KRASG12C non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms. Clin Cancer Res [Internet]. 2021;27(20):5697–707.
Subbiah V, Baik C, Kirkwood JM. Clinical Development of BRAF plus MEK inhibitor combinations. Trends Cancer [Internet]. 2020;6(9):797–810.
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Horizonte Médico (Lima)
This work is licensed under a Creative Commons Attribution 4.0 International License.
Horizonte Médico (Lima) (Horiz. Med.) journal’s research outputs are published free of charge and are freely available to download under the open access model, aimed at disseminating works and experiences developed in biomedical and public health areas, both nationally and internationally, and promoting research in the different fields of human medicine. All manuscripts accepted and published in the journal are distributed free of charge under the terms of a Creative Commons license – Attribution 4.0 International (CC BY 4.0).
