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. Overall design: The KL and KP cell lines were isolated and passaged from tumor nodules from intranasally CRE-recombinase-induced KL (KRAS+/LSL-G12D; LKB1fl/fl) and KP (KRAS+/LSL-G12D; Trp53fl/fl) genetically engineered mouse models. Mice were dosed daily with TNG260 (75 mg/kg of body weight) or the vehicle via oral gavage. They also received 200 mg anti-PD-1 (BioXCell; #BE0146) and isotype control anti-IgG2a (BioXCell; BE0089) antibodies three times a week via intra-peritoneal injection. Six- to seven-week-old female and male B6(Cg)-Tyrc-2J/J (B6-albino) mice (Jackson Laboratories; strain #000058) were injected subcutaneously with 1X106 KL or KP cells, respectively, on their right flanks. A slide caliper was used to measure tumor length and width, which was used to calculate tumor volume (length x width2)/2. Mice were randomized and divided into six treatment groups once the tumor volume reached approximately 100 mm3.