Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Non-small cell lung cancer (NSCLC) is known to have poor patient outcomes due to development of resistance to chemotherapy agents and the EGFR inhibitors, which results in recurrence of highly aggressive lung tumors. Even with recent success in immunotherapy using the checkpoint inhibitors, additional investigations are essential to identify novel therapeutic strategies for efficacious treatment for NSCLC. Our finding that high levels of histone deacetylase 11 (HDAC11) in human lung tumor tissues correlate with poor patient outcome and that depletion or inhibition of HDAC11 not only significantly reduces self-renewal of cancer stem cells (CSCs) from NSCLC but also decreases Sox2 expression that is essential for maintenance of CSCs, indicates that HDAC11 is a potential target to combat NSCLC. We find that HDAC11 suppresses Sox2 expression through the mediation of Gli1, the Hedgehog pathway transcription factor. In addition, we have used highly selective HDAC11 inhibitors that not only target stemness and adherence independent growth of lung cancer cells but these inhibitors could also efficiently ablate the growth of drug-insensitive stem-like cells as well as therapy resistant lung cancer cells. These inhibitors were found to be efficacious even in presence of cancer associated fibroblasts which have been shown to contribute in therapy resistance. Our study presents a novel role of HDAC11 in lung adenocarcinoma progression and the potential use of highly selective inhibitors of HDAC11 in combating lung cancers.