Similar Datasets
Project description:RNA sequencing (RNAseq) of N/TERT2G keratinocytes transduced with TEAD inhibitor protein (TEADi) or control GFP for 12, 24 and 48 hs
2020-02-24 | GSE136876 | GEO
Project description:RNA sequencing (RNAseq) of primary keratinocytes from mouse basal cell carcinoma mice (BCC) transduced with pooled siRNAs targeting YAP1 and TAZ (siYT) or non-targeting control siRNA (siCon), and with TEADi or GFP as control
2021-06-09 | GSE156913 | GEO
Project description:EGFP (control) and TEADi expressing podocytes were generated by lentivirus transduction to analyze transcriptional signaling by YAP/TAZ-TEAD. Tetracycline-inducible TEADi is a GFP-tagged inhibitor of the interaction of YAP1 and TAZ with TEAD transcription factors. pInducer20 EGFP-TEADi was a gift from Ramiro Iglesias-Bartolome (Addgene plasmid # 140145 ; http://n2t.net/addgene:140145 ; RRID:Addgene_140145). TEADi was previously described: YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity. Yuan Y., Park J., Feng A., Awasthi P., Wang Z., Chen Q., Iglesias-Bartolome R.. Nat Commun 11, 1472 (2020). 10.1038/s41467-020-15301-0. Transcriptome profiling (RNA-Sequencing) and differential gene expression analysis of 3 independent replicates per genotype was performed. TEADi podocytes exhibit transcriptional changes compared to WT cells including downregulation of prominent YAP target genes like CTGF, CYR61 and ANKRD1.
2023-07-03 | GSE220221 | GEO
Project description:Here we investigate the effect of the dual inhibition, in KRASG12C mutated NSCLC cells, using the KRASG12Ci adagrasib (MRTX849) and the pan-TEAD inhibitor (TEADi) K-975. We show that K-975 enhances adagrasib-induced tumor cell growth inhibition in cancer cells. Mechanistically, we detect a downregulation of MYC and E2F signatures and a downregulation of the G2/M checkpoint regulation, which result in the increase of G1 and the decrease of the G2/M cell cycle phases. These data suggest that the co-inhibition of KRASG12C and YAP1-TEAD leads to a specific switch in the mechanism of cancer cell killing.
2023-05-12 | PXD039726 | JPOST Repository
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE273358 | GEO
Project description:KRAS mutations are a predominant driver of metastatic colorectal cancer (mCRC), with approximately 10% of patients harboring the KRAS p.G12C variant. Despite the development of KRASG12C (G12Ci) and EGFR (EGFRi) inhibitors such as sotorasib and panitumumab, therapeutic resistance remains a major limitation. To define resistance mechanisms, we analyzed tissue biopsies from patients treated with G12Ci+EGFRi and employed Xenium spatial transcriptomics (Xenium ST), along with comprehensive multi-omics profiling of patient-derived xenograft (PDX) models. Known genomic alterations including NRAS p. Q61K mutations and KRASG12C amplifications were observed; however, non-genomic resistance was strongly associated with activation of the YAP-TEAD pathway. Xenium ST data revealed two key tumor subpopulations: tumor intestinal stem cells (TISCs), marked by upregulation of KRAS and YAP, and neuroendocrine-like (NE) cells, which showed KRAS upregulation alone. G12Ci+EGFRi-resistant PDX models were enriched for TISCs and associated stemness programs. The addition of a TEAD inhibitor (TEADi; IAG-933) to dual therapy induced deep tumor regression and suppressed KRAS, YAP, stemness pathways; however, NE-like cells were enriched following triple therapy. These findings suggest that TEADi enhances the efficacy of KRASG12C + EGFR inhibition by targeting TISCs but may not eliminate NE-like subpopulations, which could mediate TEAD-independent resistance and represent a therapeutic challenge.
2025-09-24 | GSE308653 | GEO
Project description:KRAS mutations are a predominant driver of metastatic colorectal cancer (mCRC), with approximately 10% of patients harboring the KRAS p.G12C variant. Despite the development of KRASG12C (G12Ci) and EGFR (EGFRi) inhibitors such as sotorasib and panitumumab, therapeutic resistance remains a major limitation. To define resistance mechanisms, we analyzed tissue biopsies from patients treated with G12Ci+EGFRi and employed Xenium spatial transcriptomics (Xenium ST), along with comprehensive multi-omics profiling of patient-derived xenograft (PDX) models. Known genomic alterations including NRAS p. Q61K mutations and KRASG12C amplifications were observed; however, non-genomic resistance was strongly associated with activation of the YAP-TEAD pathway. Xenium ST data revealed two key tumor subpopulations: tumor intestinal stem cells (TISCs), marked by upregulation of KRAS and YAP, and neuroendocrine-like (NE) cells, which showed KRAS upregulation alone. G12Ci+EGFRi-resistant PDX models were enriched for TISCs and associated stemness programs. The addition of a TEAD inhibitor (TEADi; IAG-933) to dual therapy induced deep tumor regression and suppressed KRAS, YAP, stemness pathways; however, NE-like cells were enriched following triple therapy. These findings suggest that TEADi enhances the efficacy of KRASG12C + EGFR inhibition by targeting TISCs but may not eliminate NE-like subpopulations, which could mediate TEAD-independent resistance and represent a therapeutic challenge.
2025-09-24 | GSE308699 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246590 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246583 | GEO