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REGULATIONAL MECHANISM OF CELL MOTILITY AND GM‐CSF SECRETION BY P116RIP VIA MYOSIN AND CREB PHOSPHORYLATION IN HUMAN LUNG FIBROBLASTS

were treated with high concentration of gefitinib and the remaining small population of surviving cells were termed as gefitinib-resistant-persisters (GRPs). HDACs, including HDAC1 until HDAC11, were used as markers of chromatin compaction in GRP of PC9 and HCC827 cells. We injected PC9 cells into immuno-deficient mice and, once the tumor growth, we started the treatment with gefitinib. Gefitinib-resistant tumor (GRT) was established by obtaining the remaining tumor in PC9-injected mice after two weeks of gefitinib treatment. Results: Among all HDACs that were tested, we found high expressions of HDAC1, HDAC2, and HDAC5 in PC9-GRP and HCC827-GRP cells. HDAC1 mRNA and protein were also showed upregulation in PC9-GRT as compared to the naïve PC9 tumor. Importantly, treatment with HDAC inhibitor Trichostatin A increased the sensitivity of PC9 and HCC827 cells, as well as GRP cells, to gefitinib. Furthermore, inhibition of HDAC reduced stem cells factors expressions and reduced sphere numbers of GRP. Finally, HDAC1 was also highly observed in lung cancer biopsy specimens from lung cancer patients with acquired resistance to gefitinib. Conclusion: These findings suggest that HDAC inhibition by Trichostatin A might be considered to impairs the CSC features and eventually restores the sensitivity of NSCLC to EGFR-TKI.