Crizotinib and ceritinib trigger immunogenic cell death via on-target effects

Area of Science:

• Oncology
• Cancer immunology
• Pharmacology

Background:

• Immunogenic cell death (ICD) is a form of cell death with implications for cancer therapy.
• Crizotinib, an ALK inhibitor, has been shown to induce ICD in non-small cell lung cancer, potentially via off-target effects.
• Anaplastic large cell lymphoma (ALCL) is characterized by ALK activation.

Purpose of the Study:

• To investigate the potential of ALK inhibitors to induce ICD in ALK-driven cancers.
• To differentiate between on-target and off-target effects of ALK inhibitors on ICD.

Main Methods:

• Treatment of cancer cell lines with low-dose crizotinib and ceritinib.
• Assessment of ICD markers.
• Analysis of ALK activation status in cancer cells.

Main Results:

• Low-dose crizotinib and ceritinib stimulated ICD in anaplastic large cell lymphoma.
• This effect was observed in a context where ALK is activated by translocation, suggesting an on-target mechanism.
• This contrasts with high-dose crizotinib's off-target ICD induction in other cancers.

Conclusions:

• Low-dose ALK inhibitors can promote ICD through on-target mechanisms in ALK-activated lymphomas.
• These findings expand the understanding of ICD induction by targeted therapies.
• Targeting ALK in ALCL may have dual benefits: inhibiting cancer growth and stimulating anti-tumor immunity.