Acquired resistance to MEK-CDK4/6 inhibitor combinations in cutaneous melanoma
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ABSTRACT:
PROVIDER: PRJNA435576 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6761920.fastq.gz | Fastqsanger.gz | |||
| SRR6761921.fastq.gz | Fastqsanger.gz | |||
| SRR6761922.fastq.gz | Fastqsanger.gz | |||
| SRR6761913.fastq.gz | Fastqsanger.gz | |||
| SRR6761923.fastq.gz | Fastqsanger.gz |
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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: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:Despite overall good prognosis associated to thyroid cancer, poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated thyoid carcinomas (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 thyroid cancer cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels that were associated with proliferative activity. One of the main mechanisms of resistance to CDK4/6i is RB1 defects or inactivation. RB1 mutations were present in the 3 insensitive cell lines but were not found in 5 of the 7 tumors without phosphorylated CDK4. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors and cell lines lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.
2023-10-10 | GSE235468 | GEO
Project description:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.
2019-08-23 | GSE133567 | GEO
Project description:Combined inhibition of BRAF, MEK and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on anti-tumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a-/-Pten-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA-seq analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted pro-inflammatory macrophages and cross-priming CD103+ dendritic cells (DCs), the absence of which correlated with poor overall survival and clinical responses to ICB in melanoma patients. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo. While combined BRAF, MEK and CDK4/6 inhibition demonstrates favourable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact on anti-tumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.
2020-12-02 | GSE162467 | GEO
Project description:Background: CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers.
Methods: We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays.
Results: CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4/6i insensitivity. RB1 defects (the primary cause of intrinsic CDK4/6i resistance) were not found in 5/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes.
Conclusion: Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.
| EGAS00001007577 | EGA
Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
2021-06-06 | GSE158608 | GEO
Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
2021-06-06 | GSE158607 | GEO
Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
2021-06-06 | GSE158609 | GEO
Project description:SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors
| PRJNA450615 | ENA