TNG260, a novel small-molecule CoREST inhibitor, sensitizes STK11-mutant tumors to anti-PD-1 immunotherapy

Non-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Our in-vivo CRISPR screen identified HDAC1 as a target that, when inhibited, reversed anti-PD-1 resistance driven by loss of STK11. We developed TNG260, a potent small-molecule inhibitor of the CoREST complex, whose selectivity exceeds previously generated inhibitors in this class in preclinical studies. 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, treatment with a combination of TNG260 and pembrolizumab (NCT05887492) increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T-cell infiltration to the tumor microenvironment. This study illustrates a new, promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients. Bulk RNA sequencing profiling of STK11-null mouse KL cells treated with CoREST inhinbitor TNG260 and untreated control KL cells