TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes STK11-Mutant Tumors to Anti-PD-1 Immunotherapy.

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-defic

SUBMITTER: Ahronian LG 

PROVIDER: S-EPMC12521918 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature