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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE295685 | GEO | 2025/08/16

REPOSITORIES: GEO

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

Project description: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.

2025-08-15 | GSE298051 | GEO

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Project description:While mutations in the KRAS oncogene are amongst the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS, EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

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