HDAC3 is critical in tumor development and therapeutic resistance in Kras -mutant non–small cell lung cancer

Abstract

HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in Kras -mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1 -mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM.

Inhibition of ULK1/2 and KRASG12Ccontrols tumor growth in preclinical models of lung cancer

“…Regulate cancer metabolism through effects on triosephosphate isomerase (TPI) or altered lactate production and secretion; 2. Regulate transcription effects on histone acetylation via elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs) or effects on HDAC1/3 or some other signaling circuit remains to be determined [57][58][59][60][61][62] .…”

PROTAC chemical probes for histone deacetylase enzymes

“…The selective targeting of HDAC1 and HDAC2 has been highlighted as a potential strategy for treating B-cell acute lymphoblastic leukaemia (B-ALL), 51 while HDAC3 has recently been shown to have a critical role in tumour development in Kras-mutant non-small cell lung cancer. 52 HDAC8 has been found to be overexpressed in a number of cancers. 53 To date, a number of PROTACs have been reported capable of degrading class I HDACs.…”

Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds

“…As a class I HDAC member, HDAC3 deletes the acetyl mark from histone tails, resulting in a tightly packed and transcriptionally inactive chromatin structure [ 56 ]. HDAC3 has hence been implicated in several pathophysiological processes and disorders including different cancer types, inflammatory conditions such as rheumatoid arthritis, neurodegenerative disorders like Huntington’s and Alzheimer’s disease, diabetes, kidney diseases, as well as cardiovascular diseases [ 54 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. The exact role of HDAC3 in the various pathological conditions remains poorly understood, as potent and selective HDAC3 inhibitors have been scarce.…”