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HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq HDAC3 KO NKX2-1 KO]

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. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), 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 new 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE164755 | GEO | 2023/07/14

REPOSITORIES: GEO

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HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq HDAC3 KO p65 KO]

Project description: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. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), 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 new 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.

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Project description:Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly upregulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-kB/p65-dependent mechanism. Using genetic engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors, and resulted in enhanced T-cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines, and that combination treatment of entinostat with trametinib enhanced T-cell recruitment into lung tumors in vivo. Finally, we showed that T-cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T-cell recruitment into Kras mutant lung tumors.

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HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq trametinib entinostat treatment]

Project description:HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq trametinib entinostat treatment]

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