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

Abstract

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. Lung cancer is the leading cause of cancer related mortality in the US, with about 234,000 new cases expected to be diagnosed in 2018 and 154,000 deaths 1. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer and has notably poor survival rates 2. Early stage NSCLC is treated by surgical resection, radiotherapy or chemotherapy. Chemotherapeutic agents like gemcitabine, platinum compounds and taxanes are widely used to treat both lung adenocarcinomas as well as squamous cell carcinomas, but the success rates vary significantly 3. NSCLC in smokers generally harbor mutations in the KRAS oncogene, while mutations in EGFR gene are prevalent in NSCLC in non-smokers. NSCLC has high mutational burden, and hence immunotherapy using checkpoint inhibitors is highly beneficial to a subset of the patients 4,5. Nevertheless, a significant number of NSCLC patients do not respond to immunotherapy; hence it is imperative to identify novel therapeutic strategies to combat this disease. This notion is further strengthened by the fact that there are no effective drugs that can target KRAS mutant lung cancers; furthermore, while there are highly potent tyrosine kinase inhibitors that target mutant EGFR, patients invariably develop resistance to these inhibitors resulting in recurrence of highly drug resistant metastatic tumors 6,7. It has been proposed that cancer stem cells (CSCs) contribute to tumor initiation, dormancy, recurrence and metastasis of various tumors, including NSCLC 8,9. It has been suggested ...

Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors

“…The same is again supported by our in vitro results, disclosing an upregulation of some HDAC isoforms in NCCIT-R, compared to NCCIT-P, both at the mRNA and protein level ( Figure 3 ). The differential expression of HDAC11 is particularly interesting and deserves to be explored in further studies, given the recently reported effect of HDAC11-specific inhibitors in eliminating treatment-resistant lung adenocarcinoma cells by targeting SOX2 [ 47 ], which is amplified in the NCCIT cell line [ 48 ].…”

Functional characterization of SOX2 as an anticancer target

“…One important mechanism is that SOX2 expression in cancer cells is associated with a CSC state, which is defined as a subpopulation cells within the tumor that are shown to be more resistant toward cancer therapies. 154,241,242 For example, the tamoxifen-resistant breast cancer cells exhibit stem cell-like features with a high SOX2 level, and SOX2 knockdown restores the sensitivity toward tamoxifen, whereas SOX2 overexpression confers tamoxifen resistance. 243 Importantly, our recent study showed that MLN4924, a small molecular inhibitor of protein neddylation, 51 sensitizes otherwise resistant breast cancer cells to tamoxifen by downregulating SOX2 through inactivation of FBXW2 E3 ligase.…”

Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms

“…Interestingly, HDAC11 was the most highly induced HDAC in response to a variety of HDAC inhibitors in AML cells, suggesting it indeed may have unique and critical properties compared to other HDAC family members ( 135 ). HDAC11 inhibition has been suggested to overcome therapy resistance in lung cancer models, and while its role in resistance to targeted therapies such as approved JAK2 inhibitors in MPN is unknown, current data suggest potential for the combination of JAK2 inhibition and HDAC11 inhibition as a possible future therapeutic strategy ( 136 ).…”