Faculty, Staff and Student Publications

Language

English

Publication Date

10-15-2025

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-25-0998

PMID

40882030

PMCID

PMC12521918

PubMedCentral® Posted Date

8-29-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Humans, Mice, Lung Neoplasms, AMP-Activated Protein Kinase Kinases, Protein Serine-Threonine Kinases, Carcinoma, Non-Small-Cell Lung, Programmed Cell Death 1 Receptor, Immune Checkpoint Inhibitors, Drug Resistance, Neoplasm, Mutation, Cell Line, Tumor, Immunotherapy, Xenograft Model Antitumor Assays, Tumor Microenvironment, Female, AMP-Activated Protein Kinases

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.