ID1 overexpression increases gefitinib sensitivity in non-small cell lung cancer by activating RIP3/MLKL-dependent necroptosis.

ID1 is an oncogenic factor in cancer, but its role in relation to drug sensitivity is unclear. This study aimed to investigate the role of ID1 in drug sensitivity in non-small cell lung cancer (NSCLC). ID1 overexpression in NSCLC cells harboring either EGFR or KRAS mutation was performed and the sensitivity of NSCLC to gefitinib (ZD1839) was measured. A murine orthotopic lung carcinoma model with or without stable ID1 overexpression was developed and treated with gefitinib. Transcriptomic and bioinformatics analyses showed that ID1 overexpression promoted inflammation-related cell death but not apoptosis in gefitinib-treated NSCLC cells. ID1 induced necroptosis by triggering activation of RIP1/RIP3/MLKL pathways. Protein kinase array further suggested that ID1 overexpression maintains Akt activity in gefitinib-treated NSCLC cells, which in turn upregulated FLICE-like inhibitory protein to dissociate the caspase-8-RIP1 complex. The association of RIP1 and RIP3 further activated necroptotic cell death in gefitinib-treated NSCLC. In conclusion, ID1 overexpression in NSCLC induced cellular sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, regardless of the mutational status of NSCLC. The results may provide scientific evidence for optimizing the treatment outcomes of gefitinib for NSCLC patients.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}