Conclusion
The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.
Methods
ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells.
Results
Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK.