CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression
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ABSTRACT:
PROVIDER: PRJNA932015 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23352369_1.fastq.gz | Fastqsanger.gz | |||
| SRR23352369_2.fastq.gz | Fastqsanger.gz | |||
| SRR23352370_1.fastq.gz | Fastqsanger.gz | |||
| SRR23352370_2.fastq.gz | Fastqsanger.gz | |||
| SRR23352371_1.fastq.gz | Fastqsanger.gz |
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. Ras effectors, CDK4/6 and MEK, were identified as rational targets for combination therapy from patient tumor analyses and preclinical drug studies. In MPNST cells, low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed growth but did not shrink MPNSTs in 4 of 5 patient-derived xenografts (PDXs). By comparison, combination therapy of de novo MPNSTs in immunocompetent mice caused tumors to regress, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. While drug-resistant tumors adopted an immunosuppressive microenvironment enriched with MHC II-low macrophages, drug-sensitive tumors that regressed contained plasma cells and increased T cell clustering. In other cancers, intratumoral plasma cells are associated with better response to immune checkpoint blockade (ICB). Impressively, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 ICB therapy with some mice displaying complete tumor ablation. These results reveal a novel plasma cell-associated immune response and extended antitumor activity of combined CDK4/6-MEK inhibition in MPNSTs, which dramatically enhanced the efficacy of ICB therapy. This work highlights promising, potentially curative treatment options for MPNSTs.
2023-06-29 | GSE224656 | GEO
Project description:In most human cancers, intratumoral plasma cells connote improved patient survival and heightened anti-tumor response to immune checkpoint blockade (ICB) therapies, such as those targeting programmed death-ligand 1 (PD-L1) or programmed death 1 (PD1). Using an immunocompetent mouse model of de novo malignant peripheral nerve sheath tumors (MPNSTs), we found that plasma cells are required for successful anti-PD-L1 therapy and extended survival. In order to uncover the role of plasma cells in this response, we performed scRNA-seq of de novo MPNSTs within wild-type controls versus plasma cell-deficient AID-/-; µS-/- mice following CDK4/6-MEK inhibition. These results support our hypothesis that response to anti-PD-L1 is influenced by plasma cell infiltration into MPNSTs following CDK4/6-MEK inhibition.
2026-08-19 | GSE306038 | GEO
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| S-EPMC10528807 | biostudies-literature
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas which lack effective drugs. Previous studies support the usefulness of MEK inhibitors (MEKis) for treating RAS-driven tumors, however, the lack of preclinical assessment of MEK inhibitors in MPNSTs limit the clinical application as well as the development of combination therapy. In this study, we comprehensively evaluated 8 MEK inhibitors in terms of efficiency, safety and mechanisms of resistance for treating MPNSTs. We identified the most promising MEK inhibitor, trametinib, for the treatment of MPNSTs. Through high-throughput transcriptomic sequencing and drug screening, we discovered the upregulation of integrin signaling contributing to MEK inhibitor resistance, termed as cell adhesion-mediated drug resistance (CAM-DR). We also confirmed MET overactivation in MEKi-resistant MPNST cells. These targets are potential solutions to overcome MEKi- resistance in clinical applications.
2022-07-26 | GSE174100 | GEO
Project description:Continuous MEK and CDK4/6 inhibition is effective in pre-clinical models, nevertheless, some tumors acquire resistance that was associated with enhanced phospho S6. To characterize the mechanism mediating the upregulation of mTOR-S6 pathway in these tumors, we performed RNA sequencing and targeted panel sequencing on xenograft tumors that progressed on either MEK plus CDK4/6 inhibitors (ComboR) or control diet. Gene set variance analysis (GSVA) revealed distinct gene expression signatures between the two ComboR tumors indicating heterogeneity. However, one of the 44 shared pathways between ComboR1 and ComboR2 included upregulation of an AKT pathway gene signature. By targeted sequencing and RNA sequencing, we observed high copy number change of NRAS in ComboR1 and a third tumor sample isolated from a continuous MEK inhibitor-intermittent CDK4/6 inhibitor schedule. NRAS was confirmed to mediate increased mTOR-S6 pathway activation suggesting that while distinct mechanisms are employed by melanoma tumors to circumvent MEK plus CDK4/6 inhibition, those resistance pathways eventually converge upon phosphorylation of S6 protein.
2018-04-05 | GSE111005 | GEO
Project description:Since direct pharmacological inhibition of RAS has thus far been unsuccessful, we explored system biology approaches to identify synergistic drug combination(s) that can mimic direct RAS inhibition. Leveraging an inducible mouse model of NRAS-mutant melanoma, we compare pharmacological MEK inhibition to complete NRAS-Q61K extinction in vivo. NRAS-Q61K extinction leads to a complete and durable tumor regression by enhancing both apoptosis and cell cycle arrest. By contrast, MEK inhibition only produces tumor stasis at best and we find that it robustly activates apoptosis but does not significantly impede proliferation. We used microarrays to determine which transcripts were affected by NRAS-Q61K extinction but insufficiently by MEK inhibition. We selected a single comparative timepoint, 4 days post-treatment. Downstream analyses included GSEA and TRAP algorithms, leading to the identification of a differentially affected CDK4-driven proliferation network. Immune genes were also identified as significant, but control experiments determined these to be largely the off-target effects of doxycycline and not of NRAS-Q61K extinction. The iNRAS-475 mouse melanoma cell line was injected intradermally into nude mice which were fed 2mg/ml doxycycline water. Tumors were allowed to reach 200-500mm3 after 6 weeks. Mice were then treated with vehicle or 100mg/kg of the AZD6244 MEK inhibitor, or doxycyline was withdrawn from the diet. Each sample represents a distinct tumor and thus provide six biological, not technical replicates per cohort.
2012-08-08 | E-GEOD-39984 | biostudies-arrayexpress
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.
2015-08-13 | E-GEOD-71981 | biostudies-arrayexpress
Project description:Since direct pharmacological inhibition of RAS has thus far been unsuccessful, we explored system biology approaches to identify synergistic drug combination(s) that can mimic direct RAS inhibition. Leveraging an inducible mouse model of NRAS-mutant melanoma, we compare pharmacological MEK inhibition to complete NRAS-Q61K extinction in vivo. NRAS-Q61K extinction leads to a complete and durable tumor regression by enhancing both apoptosis and cell cycle arrest. By contrast, MEK inhibition only produces tumor stasis at best and we find that it robustly activates apoptosis but does not significantly impede proliferation. We used microarrays to determine which transcripts were affected by NRAS-Q61K extinction but insufficiently by MEK inhibition. We selected a single comparative timepoint, 4 days post-treatment. Downstream analyses included GSEA and TRAP algorithms, leading to the identification of a differentially affected CDK4-driven proliferation network. Immune genes were also identified as significant, but control experiments determined these to be largely the off-target effects of doxycycline and not of NRAS-Q61K extinction.
2012-08-09 | GSE39984 | GEO
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance.
2015-08-13 | GSE71981 | GEO
Project description:We have performed gene expression profiling of tumor samples from patients included in a clinical trial of immune checkpoint inhibition for advanced MPNSTs.
2026-03-13 | GSE301187 | GEO