TNBC response to CDK4/6 inhibitors plus RANKL inhibitors
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ABSTRACT:
PROVIDER: PRJNA1162906 | ENA |
REPOSITORIES: ENA
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Project description:CDK4/6 inhibitors plus RANKL inhibitors in syngeneic TNBC model
| PRJNA1162907 | ENA
Project description:CDK4/6i alone have proven to be largely ineffective in TNBC, even in the presence of functional retinoblastoma protein (pRB). In this study, we investigated the role of the RANK pathway in the response to CDK4/6i in pRB-proficient TNBC. Transcriptomic analysis of xenografts revealed that combining CDK4/6i with RANKLi more effectively arrested the cell cycle.
2025-05-20 | GSE277615 | GEO
Project description:CDK4/6i alone have proven to be largely ineffective in breast cancer, even in the presence of functional retinoblastoma protein (pRB). In this study, we investigated the role of the RANK pathway in the response to CDK4/6i in pRB-proficient TNBC. Transcriptomic analysis of allografts revealed that combining CDK4/6i with RANKLi more effectively mounts an anti-tumoral immune response.
2025-05-20 | GSE277614 | GEO
Project description:The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the first mass spectrometry-based experiment linked to this project, we explored the proteome and phosphoproteome of WT vs CDK4 KO in triple negative breast cancer cells (MDA-MB-231).
2024-11-26 | PXD046326 | Pride
Project description:The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the third mass spectrometry-based experiment linked to this project, we assayed the proteome and phosphoproteome of purified mitochondria-ER junctions in WT and Cdk4 KO triple negative breast cancer cells (MDA-MB-231).
2024-11-26 | PXD046327 | Pride
Project description:The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the second mass spectrometry-based experiment linked to this project, we used TMT technology to assay the proteome and phosphoproteome of WT and Cdk4 KO cells triple negative breast cancer cells (MDA-MB-231) subjected to mitophagic stress, i.e. a treatment with Oligomycin + Antimycin A.
2024-11-26 | PXD046353 | Pride
Project description:CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis for hormone-positive (HR+) breast cancer patients. However, the emergence of drug resistance severely limits their long-term efficacy, and CDK4/6i monotherapy remains largely ineffective against triple-negative breast cancer (TNBC). Here, we demonstrate that combining CDK4/6i with CDK7 inhibitors (CDK7i) offers a promising therapeutic strategy to overcome resistance in both HR+ breast cancer and TNBC. Kinetic analyses reveal that CDK7i primarily targets RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance by amplifying E2F activity following the degradation of the retinoblastoma protein. Consequently, the combination of CDK4/6i and CDK7i synergistically suppresses E2F activity and inhibits the growth of drug-resistant tumors. Furthermore, this combination stimulates immune response pathways and cytokine production in cancer cells, enhancing anti-tumor immunity. These findings provide critical insights into evolving CDK inhibition strategies and highlight the therapeutic application of CDK7i in breast cancer management.
2024-11-07 | GSE281158 | GEO
Project description:Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2- BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1+ TAMs may favor resistance to CDK4/6 inhibitors in HR+HER2- BC patients.
2025-05-09 | GSE296798 | GEO
Project description:Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2- BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1+ TAMs may favor resistance to CDK4/6 inhibitors in HR+HER2- BC patients.
2025-05-09 | GSE296805 | GEO
Project description:The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit. Indeed, such CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern and the molecular mechanisms of such resistance remain undefined. Here, we demonstrate that reactivation of mTORC1 signaling through increased expression of the amino acid transporter, SLC36A1, drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms; 1) Rb loss which drives SLC36A1 via reduced suppression of E2f; 2) FXR1 overexpression which promotes SLC36A1 translation and subsequently mTORC1. Finally, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma.
2021-04-13 | GSE113268 | GEO