Data from TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i>-Mutant Tumors to Anti–PD-1 Immunotherapy

Abstract

<div>Abstract<p>Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene <i>STK11</i> are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an <i>in vivo</i> CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of <i>STK11</i> 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 <i>STK11</i>-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in <i>STK11</i>-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with <i>STK11</i>-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 <i>STK11</i>-mutant NSCLC.</p>Significance:<p>Targeting CoREST with TNG260 sensitizes <i>STK11</i>-deficient non-small cell lung cancer to anti-PD-1 immunotherapy, offering a potential treatment for patients not served by existing therapies.</p><p><a href="https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-25-4003" target="_blank"><i>See related commentary by Lin and Shen, p. 3821</i></a></p></div>