Brigatinib activates inflammasomes: Implication for immune-related adverse events

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) treat ALK-positive non-small cell lung cancer.
• Brigatinib is an ALK TKI associated with severe adverse effects potentially involving immune activation.
• Mechanisms of brigatinib-induced immune-related adverse effects are not fully understood.

Purpose of the Study:

• To investigate the direct inflammasome activation by brigatinib and other ALK TKIs.
• To analyze inflammasome activation by drug-treated liver cell supernatants.
• To elucidate brigatinib's role in immune-related adverse events.

Main Methods:

• Differentiated THP-1 cells were used to assess direct inflammasome activation by brigatinib and other ALK TKIs (crizotinib, alectinib, ceritinib).
• Supernatants from functional liver cell (FLC)-4 cells treated with these drugs were analyzed for inflammasome-activating potential.
• Levels of damage-associated molecular patterns (DAMPs) in FLC-4 cell supernatants were measured.

Main Results:

• Brigatinib directly activated inflammasomes in THP-1 cells, inducing IL-1β production and caspase-1 activation.
• Other ALK TKIs did not induce inflammasome activation.
• Supernatants from brigatinib-treated FLC-4 cells activated inflammasomes in THP-1 cells.
• Brigatinib increased DAMPs (HSP90, S100A6) in FLC-4 cell supernatants.

Conclusions:

• Brigatinib directly activates inflammasomes, unlike other ALK TKIs.
• Brigatinib induces DAMP release from hepatocytes, which then activate inflammasomes.
• This DAMP-mediated inflammasome activation pathway may underlie brigatinib-induced immune-related adverse events.