Abstract 141P
Background
Brain metastasis occurs in 10% of patients with non-small cell lung cancer (NSCLC) and it is more frequent in ALK+ NSCLC, with a frequency of around 20–30% at the time of diagnosis [doi 10.18632/oncotarget.26073]. In a multinational, phase III study (ALTA-1L), brigatinib significantly improved progression-free survival, the confirmed objective response rate (ORR) and the confirmed intracranial ORR compared with crizotinib in ALK+ NSCLC patients. Interestingly, in silico studies unveiled the potential of brigatinib in modulating proteins associated with metastasis [doi 10.18632/oncotarget.27875], however the molecular mechanisms still need to be elucidated. The aim of the present study was the creation of in silico systems biology and artificial intelligence-based models to unveil brigatinib's effects on metastatic processes both in the primary tumor (PT) and established brain metastases (BM) of ALK+ NSCLC.
Methods
We used Therapeutic Performance Mapping System technology, based on bibliographical molecular characterization of PT with metastatic capability and BM in NSCLC cohorts, and machine learning for mathematically modelling of the pharmacological mechanisms of brigatinib in the PT and already established BM. Models were constrained with publicly available gene expression data (GSE31210 and GSE128309).
Results
The results suggest that brigatinib has the potential to successfully modulate a wide array of metastasis-involved proteins both in the PM and in BM, acting mainly through IGFR1, EGFR, FLT3, ALK and ROS1. Brigatinib modulation of the effectors of PT with metastatic capability seems to be derived from a downregulation of STAT5 and 3, CXCR4, ETS1, AKT3, CTNB1, ERBB2 and MAPK and an activation of CADH1, whereas its action on the effectors of BM seems to be derived from a downregulation of YAP1, FGFR1, ABL1, CTNB1, NFKB1 and PI3 K/AKT/mTOR pathway.
Conclusions
In silico models have revealed the potential of brigatinib to successfully modulate a wide array of metastasis-involved proteins both in the PT and in the BM. Further clinical studies are needed to validate these potential results before translation into clinical practice.
Legal entity responsible for the study
Takeda Farmacéutica España.
Funding
Takeda Farmacéutica España.
Disclosure
E. Carcereny Costa: Financial Interests, Institutional, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Roche, Takeda; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Funding: Merk; Financial Interests, Institutional, Other: Bristol-Myers Squibb, Pfizer, Roche, Takeda. L. Artigas: Financial Interests, Institutional, Full or part-time Employment: Anaxomics SL. A. López: Financial Interests, Institutional, Full or part-time Employment: Takeda Farmacéutica España. M. Coma Camprodon: Financial Interests, Institutional, Full or part-time Employment: Anaxomics SL. All other authors have declared no conflicts of interest.