Abstract 3280: Combination of MYC and class IIa HDAC inhibition potentiates anti-tumor efficacy in non-small cell lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer-related mortality among both men and women in the United States. Immune checkpoint blockade has emerged as a promising therapy for advanced non-small cell lung cancer (NSCLC); however, only a subset of patients responds to this treatment regimen. Therefore, combinatorial therapeutic strategies to enhance anti-tumor immunity and efficacy of immunotherapy are in urgent need. Our group and others have demonstrated the potential of MYC inhibition in NSCLC to render the tumor microenvironment (TME) more immune permissive by upregulating antigen presentation machinery and chemokines that recruit effector lymphocytes. We performed a dedicated reanalysis of published transcriptome data from two distinct cancer types, prostate and lung, which were treated with novel MYC inhibiting agents, MYCi975 and Omomyc, respectively. These data revealed augmentation of two class IIa histone deacetylases (HDACs), HDAC5 and HDAC9, upon MYC inhibition. In addition to the suggested interaction between MYC and Class IIa HDACs derived from our transcriptional analyses, class IIa HDACs have an established role in tumorigenesis, angiogenesis, and poor prognosis of cancer patients, thus implying that therapeutic benefits could be derived from dual inhibition of MYC and class IIa HDAC. Elucidation of the basal relationship between Class IIa HDACs and the immune microenvironment of NSCLC was derived through correlative analyses of TCGA Lung adenocarcinoma and squamous carcinoma RNA-seq data. These data revealed a conserved positive correlation across non-small cell lung cancer between class IIa HDAC RNA levels, Treg score, and Treg/CD8 ratio by immune deconvolution analysis. Evaluation of combinatorial treatment efficacy of MYCi plus Class IIa HDACi was undertaken using 19 NSCLC cell lines, which recapitulate the mutational and histological landscape of NSCLC. These data identified a genotype-driven drug synergy, wherein EGFR mutant cell lines presented as resistant, and Ras mutant cell lines presented as sensitive to our combination drug paradigm. In summary, we defined a positive association between Class IIa HDAC expression and Treg score in TCGA NSCLC samples, suggesting a possibility of immune-modulation via class IIa HDAC inhibition. Furthermore, we identified transcriptional augmentation of class IIa HDAC induced by MYC repression, which indicates a potential novel therapeutic opportunity. Finally, we determined that inhibition of class IIa HDACs potentiates MYC inhibitor-driven anti-tumor efficacy across a diverse set of NSCLC cell lines. Citation Format: Jina Park, Michelle Vaz, Ray-Whay C. Yen, Stephen B. Baylin, Michael J. Topper. Combination of MYC and class IIa HDAC inhibition potentiates anti-tumor efficacy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3280.