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Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using an in silico systems biology-based approach

2021; Impact Journals LLC; Volume: 12; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.27875

1949-2553

Enric Carcereny, Alonso Fernández-Nistal, Araceli López, Carmen Montoto, Andrea Naves, Cristina Segú-Vergés, Mireia Coma, Guillem Jorba, Baldomero Oliva, José Manuel Mas,

Pancreatic and Hepatic Oncology Research

// Enric Carcereny 1 , Alonso Fernández-Nistal 2 , Araceli López 2 , Carmen Montoto 2 , Andrea Naves 2 , Cristina Segú-Vergés 3 , Mireia Coma 3 , Guillem Jorba 3 , 4 , Baldomero Oliva 4 and Jose Manuel Mas 3 1 Catalan Institute of Oncology B-ARGO Group, Hospital Germans Trias i Pujol, Badalona, Spain 2 Takeda Farmacéutica España, Madrid, Spain 3 Anaxomics Biotech, Barcelona, Spain 4 Structural Bioinformatics (GRIB-IMIM), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain Correspondence to: Enric Carcereny, email: ecarcereny@iconcologia.net Keywords: ALK inhibitor; brigatinib; alectinib; mathematical model; systems biology Received: July 02, 2020 Accepted: December 23, 2020 Published: February 16, 2021 Copyright: © 2021 Carcereny et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Around 3–7% of patients with non-small cell lung cancer (NSCLC), which represent 85% of diagnosed lung cancers, have a rearrangement in the ALK gene that produces an abnormal activity of the ALK protein cell signaling pathway. The developed ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, ceritinib, alectinib, brigatinib and lorlatinb present good performance treating ALK+ NSCLC, although all patients invariably develop resistance due to ALK secondary mutations or bypass mechanisms. In the present study, we compare the potential differences between brigatinib and alectinib's mechanisms of action as first-line treatment for ALK+ NSCLC in a systems biology-based in silico setting. Therapeutic performance mapping system (TPMS) technology was used to characterize the mechanisms of action of brigatinib and alectinib and the impact of potential resistances and drug interferences with concomitant treatments. The analyses indicate that brigatinib and alectinib affect cell growth, apoptosis and immune evasion through ALK inhibition. However, brigatinib seems to achieve a more diverse downstream effect due to a broader cancer-related kinase target spectrum. Brigatinib also shows a robust effect over invasiveness and central nervous system metastasis-related mechanisms, whereas alectinib seems to have a greater impact on the immune evasion mechanism. Based on this in silico head to head study, we conclude that brigatinib shows a predicted efficacy similar to alectinib and could be a good candidate in a first-line setting against ALK+ NSCLC. Future investigation involving clinical studies will be needed to confirm these findings. These in silico systems biology-based models could be applied for exploring other unanswered questions.