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.
Highlights
Lung cancer (LC) remains the leading cause of death worldwide, with an estimated 1.6 million deaths each year [1, 2]
Each pathophysiological process was functionally characterized at protein level to determine its molecular effectors and used for focusing the analysis towards anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) in a human biological network context (Figure 1 and Supplementary Table 2)
Mechanistic systems biology models of brigatinib and alectinib obtained with Therapeutic performance mapping system (TPMS) technology were constructed with accuracy values of 94% to evaluate their mechanism of action and potential treatment efficacy in ALK+ NSCLC
Summary
Lung cancer (LC) remains the leading cause of death worldwide, with an estimated 1.6 million deaths each year [1, 2]. Despite significant therapeutic advances over the last decade, over half of patients diagnosed with LC die within one year of diagnosis and the fiveyear survival is around 18% [3]. About 85% of LCs are diagnosed as the subtype non-small cell lung cancer (NSCLC), adenocarcinoma being one of the most common histological subtypes. Central nervous system (CNS) metastasis is a common finding in NSCLCs, occurring in 10% of patients, and even more frequent in ALK+ NSCLCs, were the frequency of CNS metastasis is around 20–30% at the time of diagnosis [7, 8]. CNS is the most common site of relapse [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
