Conclusion
TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS.
Results
We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells.