Synergistic effects of gefitinib and thalidomide treatment on EGFR-TKI-sensitive and -resistant NSCLC

EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most if not all of the patients who initially have responded to EGFR-TKIs later experience progression or deterioration of the disease while still on the treatment. Drug resistance becomes inevitable due to the emergence of the second-site EGFR T790M mutation within exon 20, MET and HER2 amplification, small cell histologic transformation and rare secondary BRAF mutations. The acquired drug resistance limits the efficacy of EGFR-TKIs in patients. Thalidomide is a widely used anti-angiogenic and immunomodulatory drug with anticancer effects. The current study was aimed to explore the combined effects of gefitinib and thalidomide on NSCLC. The combination of thalidomide and gefitinib induced antiproliferative and proapoptotic effects in HCC827, PC9, and PC9GR cells. The inhibition of EGFR phosphorylation and downstream signaling was more pronounced in the thalidomide and gefitinib co-treatment group as compared with the single agent treatment groups. Further study revealed that the inhibitors of AKT, MEK/ERK, and p38 increased the antiproliferative and proapoptotic effects of the combined treatment of thalidomide and gefitinib. However, JNK inhibition moderately abrogated cell apoptosis induced by the co-treatment. In conclusion, thalidomide and gefitinib exhibit synergistic effects on both TKI-sensitive and -resistant NSCLC cells by targeting the EGFR signaling pathways, suggesting that the combination strategy is promising for the treatment of NSCLC.