A Novel Histone Deacetylase Inhibitor Synergistically Enhances The Antitumor Activity Of Erlotinib In EGFR-TKI-Resistant NSCLC Cells

Lung cancer is one of the most common maliganancy in the worldwide with the highest cancer incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer. Epidermal growth factor (EGFR) plays an important role in the development of non-small cell lung cancer, and abnormal expression of EGFR are founded in a number of non-small cell lung cancer. The FDA has approved targeting -EGFR inhibitors (TKI),such as gefitinib and erlotinib for the treatment of non-small cell lung cancer, but the responses are not durable, as tumors will gradually produce resistance with medication progress, which greatly limits the clinical application of the drug. New strategies to overcome resistance of EGFR-TKIs are clinically desireble. Histone deacetylase inhibitor (HDACi) are a new class of inhibitors by targeting epigenetics, affecting tumor cell proliferation, apoptosis, cell cycle, migration, angiogenesis. In this study, we used a novel HDAC inhibitors YF454A combined with erlotinib to explore the role in NSCLC. We found a significant synergistic inhibition for EGFR-TKI-resistant non-small cell lung cancer growth. In erlotinib-resistant cells PC9/R cell lines and A549 bearing tumor models, erlotinib and YF454A oral administration of 25mg/kg/d respectively, two monotherapy group did not significantly inhibit tumor growth (p>0.05), while combination group showed significantly tumor growth inhibition (p<0.001). Treated mice didn’t show significant body weight change. Further in vitro experiments showed that erlotinib combined with YF454A could significantly inhibit the proliferation of NSCLCs-A549, H1975, H1299, HCC827/R, PC9/R, induce their apoptosis, and inhibit colony formation. The in vivo and in vitro effects do not depend on EGFR and Ras mutation status. In terms of the molecular mechanisms, we found that the combination significantly inhibited EGFR downstream signaling pathways, inhibiting AKT and ERK phosphorylation. And the combination significantly reduced the EGFR-TKI resistance-associated protein AXL, c-Met, Her2 expression. In summary, YF454A can significantly increase non-small cell lung cancer sensitivity for erlotinib. A novel HDAC inhibitor YF454A combined with erlotinib to treat EGFR-TKI-resistant non-small cell lung cancer shows promising.