Crizotinib - a tyrosine kinase inhibitor that stimulates immunogenic cell death.
Peng LiuLiwei ZhaoOliver KeppGuido KroemerPublished in: Oncoimmunology (2019)
Crizotinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancers (NSLCL) and lymphomas expressing activating translocations or mutations of oncogenic tyrosine kinases (in particular ALK and ROS1). We recently observed that high-dose (final concentration in vivo: ~10 µM) crizotinib can induce immunogenic cell death (ICD) in cancer cells lacking ALK/ROS1 activation through off-target effects that require the inhibition of several other tyrosine kinases. When combined with cisplatin (which alone does not induce ICD), crizotinib sensitizes NSCLC models to subsequent immunotherapy with PD-1 blockade, allowing to cure more than 90% of established orthotopic cancers. Of note, simultaneous treatment of mice with cisplatin, crizotinib and PD-1 blocking antibodies causes acute hepatotoxicity that can be avoided by a sequential regimen involving initial treatment with cisplatin plus crizotinib, followed by PD-1 blockade one week later. It will be important to translate these results obtained in mice into a clinical trial in NSCLC patients.
Keyphrases
- advanced non small cell lung cancer
- cell death
- epidermal growth factor receptor
- clinical trial
- high dose
- small cell lung cancer
- low dose
- dna damage
- intensive care unit
- randomized controlled trial
- type diabetes
- combination therapy
- single cell
- tyrosine kinase
- transcription factor
- oxidative stress
- hepatitis b virus
- high fat diet induced
- young adults
- endoplasmic reticulum stress
- wild type