Product Description

Brigatinib is an oral, potent, and selective ALK inhibitor indicated for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) who have experienced disease progression or intolerance following crizotinib therapy.

Screeningbio‘s NCI-H2228/Brigatinib resistance cell line generated by exposing to increasing concentration of drug for certain period of time. After stable acquire resistance, cells were harvested and characterized for drug resistance by 7 days proliferation assay.

Data

Target Background

Brigatinib (Alunbrig) is a next‑generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK‑positive non‑small cell lung cancer (NSCLC). It selectively binds to the ALK kinase domain, including several resistant mutants, and also inhibits ROS1. By blocking downstream signaling pathways such as STAT3, PI3K/AKT, and MAPK, brigatinib induces sustained cell cycle arrest and apoptosis in ALK‑driven tumors. However, acquired resistance inevitably develops, limiting its long‑term efficacy in patients who initially respond.

Mechanistically, brigatinib resistance arises through multiple cellular adaptations. Secondary mutations within the ALK kinase domain—particularly the solvent‑front mutation G1202R, the gatekeeper L1196M, and compound mutations like G1202R + L1196M—reduce drug binding affinity and reactivate ALK signaling. Bypass pathway activation, including c‑MET amplification, EGFR activation, KRAS mutations, or engagement of IGF‑1R and SRC signaling, provides alternative survival routes independent of ALK. Upregulation of drug efflux transporters such as P‑glycoprotein (ABCB1) and ABCG2 decreases intracellular brigatinib accumulation. In addition, phenotypic changes including epithelial–mesenchymal transition (EMT), enhanced autophagy, and activation of pro‑survival NF‑κB signaling further contribute to reduced drug sensitivity.

Understanding these mechanisms is critical for designing strategies to overcome brigatinib resistance, such as developing fourth‑generation ALK inhibitors active against compound mutations, combining brigatinib with bypass pathway inhibitors (e.g., c‑MET, SRC, or MEK inhibitors), co‑administering efflux transporter modulators, or employing patient‑derived resistant cell models to guide personalized therapy and optimal sequencing of ALK inhibitors.