Abstract
Abstract CRISPR-based functional genomics screening can be designed to identify novel cancer cell intrinsic targets that increase tumor immunogenicity. Using a FACS-based CRISPR sorting screen for PD-L1 expression, we identified Euchromatic histone-lysine-N-methyltransferase 1 and 2 (EHMT1/2) as negative modulators of the interferon signaling pathways. EHMT1 and EHMT2 are histone methyltransferases that mono- and di-methylate lysine 9 of histone H3 to repress gene transcription of defined target genes. Gene knockout or pharmacological inhibition of EHMT1/2 in cancer cells resulted in de-repression of gene promoters, upregulation of interferon-stimulated genes (ISGs), and secretion of pro-inflammatory cytokines. Here, we present the preclinical characterization of TNG917 - an oral and highly selective EHMT1/2 inhibitor with low nanomolar cellular potency, and favorable pharmacodynamic and pharmacokinetic properties. In humanized and syngeneic mouse models, treatment with TNG917 in combination with anti-PD1 promoted a T-cell-infiltrated tumor microenvironment, led to significant anti-tumor activity, and resulted in survival benefit. In summary, our in vitro and in vivo studies provide a rationale for the clinical development path of TNG917, in combination with checkpoint inhibition, in patients with immune cold tumors. Citation Format: Alvin Lu, Brian Haines, Ji Lei, Wenhai Zhang, Minjie Zhang, Douglas A. Whittington, Maria Lucia Ferdinez, Yi Yu, Samuel R. Meier, Ashley Choi, Alborz Bejnood, Madhavi Bandi, Katherine Lazarides, Xuewen Pan, Lina Gu, Alice W. Tsai, Sirimas Sudsakorn, Colin Liang, Jon Come, Brett Williams, Scott Throner, Joseph Vacca, John P. Maxwell, Jannik N. Anderson, Alan Huang, Chengyin Min, Yingnan P. Chen. TNG917 is a clinical-grade, potent and selective inhibitor of EHMT1/2 for the treatment of immune cold tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3242.
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