Abstract ND12: TNG260: A novel, orally active, CoREST-selective deacetylase inhibitor for the treatment of STK11-mutant cancers

Abstract STK11 loss of function mutations occur in 12-15% of lung adenocarcinoma and have been shown to drive resistance to immune checkpoint blockade in patients and preclinical models. STK11-deficient syngeneic mouse tumor models reflect this biology and are insensitive to anti-PD1 treatment. Informed by in vivo CRISPR-based screens, histone deacetylase 1 (HDAC1) was identified as a target gene, which when knocked out in tumor cells, reverses anti-PD1 resistance driven by STK11 tumor suppressor gene loss. Here, we describe the discovery and development of TNG260 as a potent and selective inhibitor of the HDAC1-containing complex CoREST. TNG260 inhibits CoREST deacetylase activity with 500-fold selectivity over the other HDAC1-containing complexes, NuRD and Sin3, and the HDAC3-containing complex NCoR. In preclinical studies, selective CoREST inhibition by TNG260 results in transcriptional reprogramming of STK11-mutant tumor cells, altering tumor cell cytokine secretion and markedly reducing recruitment of suppressive Treg cells to STK11-mutant tumors. Moreover, TNG260, in combination with anti-PD1 treatment, drives durable tumor regressions in multiple syngeneic STK11-mutant xenograft models. TNG260 has no anti-tumor efficacy in athymic mice, indicating the responses with TNG260 are mediated by T cells. Unlike previously developed pan-HDAC inhibitors, which are directly cytotoxic to cancer (and immune) cells, IND-enabling toxicology studies in rat and dog showed that TNG260 was well-tolerated at exposures predicted to be efficacious in humans, with bone marrow suppression only detectable at doses where TNG260 is no longer selective for CoREST inhibition. TNG260 clinical development will be among the first to combine the power of genetic patient selection and immunotherapy, evaluating patients with STK11 mutant cancers in a trial combining TNG260 and a checkpoint inhibitor. Citation Format: Leanne G. Ahronian, Minjie Zhang, Chengyin Min, Alice W. Tsai, Jacques Ermolieff, Patrick McCarren, Margaret Wyman, David Guerin, Ye Wang, Alborz Bejnood, Kenjie Amemiya, Brian McMillan, Nikitha Das, Preksha Shahagadkar, Brian Doyon, Andre Mignault, Colin Liang, Vassil Elitzin, Samuel R. Meier, Ashley Choi, Yi Yu, John P. Maxwell, Brian B. Haines, Jannik N. Andersen, Heather DiBenedetto, Aaron Weitzman, Alan Huang, Xinyuan Wu. TNG260: A novel, orally active, CoREST-selective deacetylase inhibitor for the treatment of STK11-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND12.