TNG260, a novel small-molecule CoREST inhibitor, sensitizes STK11-mutant tumors to anti-PD-1 immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1267170 | ENA |
REPOSITORIES: ENA
Similar Datasets
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.
2025-08-16 | GSE295685 | GEO
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
Project description:TNG260, a novel small-molecule CoREST inhibitor, sensitizes STK11-mutant tumors to anti-PD-1 immunotherapy
| PRJNA1255586 | ENA
Project description:STK11/LKB1 and KEAP1 mutations are associated with immunotherapy resistance. We employed KRAS syngeneic mouse cells (K) and generated KEAP1 loss (KK) or STK11/KEAP1 loss (KLK) by CRISPR/KO. Then we injected these tumor cells and collected the tumor for single-cell RNA-seq. Our aim is to analyze the impact of STK11 and/or KEAP1 deficiency on the immune microenvironment.
2024-05-20 | GSE267321 | GEO
Project description:p38MAPKa stromal reprogramming sensitizes metastatic breast cancer to immunotherapy
| PRJNA865030 | ENA
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.
2015-10-21 | GSE72094 | GEO
Project description:Transcriptional profiling of BL/6 mice harboring a mutant Kras allele, with or without knockouts of Stk11 and/or Keap1, or with expression of an Nfe2l2 transgene, Nrf2Tg. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.
2020-01-31 | GSE133714 | GEO
Project description:HCC515 lung cells with dox-inducible KEAP1 knockdown and/or STK11 re-addition, under two different metabolic stress conditions, baseline vs. suspension, were transcriptionally profiled to investigate whether KEAP1 knockdown can rescue metabolic defects in STK11-null cancer cells and how the regulation of the transcriptome by KEAP1 knockdown is affected by STK11 status and different metabolic stress conditions. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.
2020-01-31 | GSE133715 | GEO
Project description:We performed RNA-sequencing of mouse cells derived from colony forming assays (CFA) to evaluate the transcriptome of MPN cells with deletion of the tumor suppressor STK11/LKB1 and relative controls. The CFA are from mouse primary floxed STK11 hematopoietic stem and progenitor cells (HSPCs) transduced with retroviruses encoding the MPN mutation MPLW515L and CRE recombinase to delete STK11.
2021-01-27 | GSE159737 | GEO
Project description:Mutagenesis sensitizes murine models of triple negative breast cancer to immunotherapy
| PRJNA561596 | ENA