TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes STK11 -Mutant Tumors to Anti–PD-1 Immunotherapy
Year: 2025
Type: article
Abstract: Patients with non-small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers in a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T-cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in patients with STK11-mutant NSCLC. SIGNIFICANCE: Targeting CoREST with TNG260 sensitizes STK11-deficient non-small cell lung cancer to anti-PD-1 immunotherapy, offering a potential treatment for patients not served by existing therapies. See related commentary by Lin and Shen, p. 3821.
Source: Cancer Research
Authors: Leanne G. Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S. Patel, Ke Geng, Reshmee Bhattacharya, Gerald S. Falchook, Jonathan W. Goldman, Alexander I. Spira, Salman R. Punekar, David R. Spigel, Judy S. Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M. Powell, Alfonso Lopez, Michela Ranieri, Magdalena A. Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick McCarren, Alice Tsai, Suleman S. Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M. Das, Lauren R. Flynn, Julie A. Shields, Laney Danielczyk, Brian J. McMillan, Andre Mignault, Samuel R. Meier, Hsin-Jung Wu, David J. Guerin, Douglas A. Whittington, Chengyin Min, Iga Sienczylo, John P. Maxwell, Heather J. DiBenedetto, Hideo Watanabe, Brian B. Haines, Alan Huang, Adam Crystal, Jannik N. Andersen, Xinyuan Wu, Kwok-Kin Wong
Institutions: Tango Therapeutics (United States), NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, HealthONE, University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, Virginia Cancer Specialists, The US Oncology Network, New York University, Sarah Cannon, Florida Cancer Specialists & Research Institute, The University of Texas MD Anderson Cancer Center, The University of Texas Southwestern Medical Center, Jnana Therapeutics (United States)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, International Association for the Study of Lung Cancer, Celgene, NYU Langone Medical Center, Regeneron Pharmaceuticals, Merck KGaA, Jazz Pharmaceuticals, Novocure, Agios Pharmaceuticals, Mersana Therapeutics, BeiGene, Incyte, Calithera Biosciences, Syndax Pharmaceuticals, NGM Biopharmaceuticals, Revolution Medicines, Relay Therapeutics, Compass Therapeutics, Moderna, MacroGenics, Seagen, Astellas Pharma, European Society for Medical Oncology, National Institutes of Health, Genentech, University of Texas MD Anderson Cancer Center, Chugai Pharmaceutical, Takeda Oncology, Ignyta, Loxo Oncology, Foundation Medicine, National Cancer Institute, Janssen Pharmaceuticals, Daiichi Sankyo Europe
OpenAlex ID: W4413818083