TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity.
Hayato OguraYuka Nagatake-KobayashiJun AdachiTakeshi TomonagaNaoya FujitaRyohei KatayamaPublished in: Scientific reports (2017)
ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells. Two resistant cell lines with CD74-ROS1 F2004V or F2075C mutations, which are homologous to ALK F1174 or F1245 mutations, survived in the presence of a low dose of ROS1-TKI. Removal of ROS1-TKI from these TKI-addicted cells induced excessive activation of ROS1 tyrosine kinase followed by apoptosis. We succeeded in recapturing the TKI-addicted phenotype using doxycycline-inducible CD74-ROS1 mutant over-expression in Ba/F3 cells, suggesting that excessive ROS1 oncogenic signaling itself induced apoptosis instead of cell growth. Phosphoproteomic analysis and high-throughput inhibitor screening revealed that excessive ROS1 signaling in the TKI-addicted cells phosphorylated or activated apoptosis-related molecules such as FAF1 or p38. Collectively, our findings partly clarify molecular mechanisms of excessive ROS1 oncogenic signaling that mediates paradoxical induction of apoptosis.
Keyphrases
- induced apoptosis
- cell death
- cell cycle arrest
- tyrosine kinase
- endoplasmic reticulum stress
- dna damage
- reactive oxygen species
- oxidative stress
- advanced non small cell lung cancer
- signaling pathway
- low dose
- epidermal growth factor receptor
- high throughput
- stem cells
- weight gain
- crispr cas
- diabetic rats
- dna repair
- mesenchymal stem cells
- high intensity
- single cell
- young adults
- physical activity
- high glucose
- body mass index
- weight loss