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Immune checkpoint blockades (ICBs) are known as a promising treatment option against in advanced non-small-cell lung cancer (NSCLC). And KRAS is the most frequently mutated oncogene in NSCLC. However, KRAS mutation is not a significantly associated with survival benefit of ICBs. Mutations in LKB1 (aka STK11) and frequently co-occurring KRAS mutations are accompanied with poor survival in metastatic NSCLC immuno-oncology trials. Even tumor mutational burden is a proposed-potential biomarker for response to ICBs, there are therapeutic unmet needs in NSCLC patient with KRAS/LKB1 (KL) mutation. Epigenetic regulation lead to enhanced anti-tumor immunity of innate immune responses via inducing type I interferons. Also it drives to enhance adaptive immune responses by targeting T cell recognition factors as well as recruitment immune cells to tumor microenvironments (TMEs). Thus, we demonstrated the pharmacological inhibition of Enhancer of zeste homolog (EZH)1/2 enhance the efficacy of clinically available immunotherapies in KRAS/LKB1 mutated NSCLC. Previously, we reported that a novel EZH1/2 dual inhibitor, HM97662, has showed potently decreased global H3K27me3 and strong anti-proliferative activities against various hematological cancer cell lines with EZH2 activating mutations as well as solid tumor cell lines with negatively mutated components of regulatory protein complexes. In this study, we evaluated that HM97662 could induce of STING expression and STING-dependent cytokine production in KL mutant NSCLC cell lines. Furthermore, we explored anticancer effect by inducing immune modulation by EZH2 inhibitors in combination with an anti-PD-(L)1 agent was evaluated. As a result, HM97662 potently restored STING expression in KL mutated cell lines such as A549 and H460, but did not KRAS/p53 (KP) mutated H358 cells. HM97662 also dose-dependently increased the mRNA expression of CXCL10, IFN-α and IFN-β and secretion of CXCL10, IFN-α, CCL2, CCL3 and CCL5 at nanomolar concentrations in H460 cells. In accordance with this, HM97662 showed potent growth inhibition against H460 cells under co-culture condition with activated T cells. Moreover, HM97662 had superior anti-proliferation efficacy among the tested compounds in H460 cells with activated T cells, when it combined with anti-PD-L1 antibody avelumab. In our exploratory study, HM97662 increments the sensitivity of immune checkpoint inhibitor by restoration of STING expression and STING pathway related chemo/cytokine production in KRAS/LKB1 mutated NSCLC cell lines. These results demonstrate that HM97662 drives anti-cancer effect by immune modulation in combination with anti-PD-(L)1 agent, suggesting therapeutic potency to combination with ICBs by turning non-inflamed to inflamed TME. Clinical trials to prove the effectiveness of HM97662 identified in preclinical studies need to be carried out immediately. Citation Format: Jooyun Byun, DongJin Hong, Miyoung Lee, Soonho Kweon, Seung Hyun Jung, Yu-Yon Kim, Hyunjin Park, Junghwa Park, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Overcoming immune checkpoint blockade resistance via EZH1/2 dual inhibition by HM97662 in KRAS/LKB1 mutated NSCLC [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 3276. |
