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Longitudinal monitoring of BRAFV600-mutant melanoma patients on treatment reveals specific macrophage population mediating targeted therapy resistance

ABSTRACT: Although treatment of melanoma patients with BRAF and MEK inhibitors has demonstrated impressive clinical outcomes, innate or acquired resistance to targeted therapy remains a major challenge. To uncover resistance mechanisms in patients, we performed single cell RNA sequencing of longitudinal biopsies of the same tumors from four consenting melanoma patients before the start of BRAFi/MEKi treatment and at different time points during treatment. Among the genes most differentially expressed between malignant cells from resistant vs. responding patients was POSTN encoding the secreted factor periostin. POSTN was predicted to predominantly signal to a macrophage population associated with targeted therapy resistance (TTR) in patients and was able to polarize macrophages towards a TTR phenotype. Finally, polarized TTR macrophages protected melanoma cells from MEKi-induced killing, which involved CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages might represent a strategy to overcome targeted therapy resistance in melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229908 | GEO | 2023/12/01

REPOSITORIES: GEO

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BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells – insights into mode of action and resistance mechanisms

Project description:About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid anti-tumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate anti-tumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In this study, the MEKi binimetinib, cobimetinib, and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib, and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using 2D and 3D cell culture models and transcriptome analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the anti-proliferative and pro-apoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the “don’t eat me signal” molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, this study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.

2023-11-14 | GSE245262 | GEO

Serum IGF1 is a new prognostic marker for resistance to targeted therapies and a predictive marker for anti-IGF1R therapy in melanoma

Project description:In a prospective clinical study, we show that increased serum IGF1 levels in a patient may be a predictive marker of melanoma escape to therapies targeting MAPK pathway (BRAFi/MEKi). In addition, our in vitro and in vivo studies suggest that the response of targeted therapies-resistant melanoma cells to IGF1R inhibitor appears to correlate with the level of IGF1 secretion. Overall, our results suggest that monitoring serum IGF1 levels would individually identify melanoma patients who escape BRAFi/MEKi treatment and may benefit from a combination of targeted therapies and IGF1 signaling inhibition to overcome resistance.

2023-10-30 | GSE239284 | GEO

SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy

Project description:Oncogenic KRAS signaling is a hallmark of pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with few treatment options. A major roadblock in deploying therapies targeting the KRAS-MAPK pathway is the rapid emergence of resistant cancer cells. However, molecular mechanisms underlying adaptive targeted therapy resistance in PDAC are poorly understood. Here we find SETD5 (SET domain containing 5) as a major epigenetic driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is identified in a genetic screen of annotated methyltransferases that mediate MEKi toxicity in PDAC cells. SETD5 expression is induced upon PDAC cells and tumors acquring MEKi-resistance and SETD5 deletion restores vulnerability of refractory PDAC to MEKi therapy in mouse models and patient-derived xenografts (PDX). SETD5 lacks intrinsic histone methyltransferase activity and rather scaffolds a distinct corepressor complex that regulates HDAC3 and G9a catalytic behaviors to couple selective deacetylation with methylation of histone H3 at lysine 9 (H3K9). Gene silencing by the SETD5 complex regulates a network of known drug resistance pathways to reprogram cellular responses to MEKi, a resistance program disrupted by G9a and HDAC3 blockade. Combinatorial pharmacological targeting of MEK1/2, G9a, and HDAC3 results in sustained tumor growth inhibition in murine and human models of PDAC. Together, our work uncovers SETD5 as a master epigenetic regulator of acquired MAPK-pathway therapy resistance and suggests an efficacious clinical path for MEKi in PDAC.

2020-05-06 | GSE142046 | GEO

Ccr2+ monocyte-derived macrophages influence trajectories of acquired therapy resistance in Braf-mutant melanoma

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2023-05-09 | GSE226835 | GEO

Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance: elevated P2RX7 levels indicate response to targeted therapy

Project description:While effective therapy is available for melanoma patients harbouring BRAF mutations, to date, the efficient therapeutic approaches for NRAS-mutant melanoma patients are limited. Therapeutic regimen involving combinatorial inhibition of MEK1/2 and CDK4/6 prove to be beneficial as targeted therapy for NRAS-mutant melanoma. Yet, only a subset of melanoma patients responded to this treatment, whereas acquired resistance eventually emerge in responders. Upon prolonged therapy with MEK1/2 and CDK4/6 inhibitors cells switch to fully drug-resistant or senescent phenotype in vitro. Consequently, there is a necessity to portray cell populations sensitive to targeted therapy, but also cell transitions associated with NRAS-mutant melanoma resistance. To define transcriptional states arising under indicated therapy and cell fate decisions governing resistance, we performed single-cell RNA sequencing at four distinguished time points during treatment. In this study, we identified a cell population highly enriched in calcium signalling, among others, associated with positive drug response. In particular, prolonged expression of ATP-gated ion channel P2RX7 was related to a senescent-like phenotype. Next, we described an immune-like melanoma state that acquired drug resistance and re-enter the cell cycle under treatment, as well as cell populations with intrinsic potential to evade drug pressure.

2023-04-26 | GSE230538 | GEO

Targeted Next-Generation Sequencing for profiling frequently mutated genes in early-stage colon cancer

Project description:Intratumor heterogeneity fosters the evolution of the genome leading to metastatic progress and therapy resistance. Here, we investigate the relative contribution of genomic heterogeneity involving mutations and CNAs as prognostic and predictive determinants for disease recurrence in early-stage colon cancer. We combined targeted next-generation sequencing (NGS) and SNP arrays on a retrospective cohort of untreated stage II colon cancer patients to assess the association of genomic subclonality with time to recurrence (TTR).

2021-12-01 | GSE172190 | GEO

Spectrum, clinical correlates and clinical implications of BRAF-inhibitor resistance mechanisms in melanoma

Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes. Total RNA was obtained from fresh-frozen melanoma tumour samples from patients before commencing treatment with dabrafenib or vemurafenib and at time of tumour progression.

2014-02-19 | E-GEOD-50509 | biostudies-arrayexpress

Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I

Project description:MEK1/2 inhibitors (MEKi) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in PNF patients. We determined the efficacy of 6 different MEKi for treating PNFs, explored drug resistance mechanisms and identified potential combination therapies to overcome resistance. By screening drug efficacy among 6 MEKi in human NF1-deficient PNF cell lines, TAK-733 was found reduce PNF cell viability the most. We then cultured the TAK-733 resistant cells and explored potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors (CDKi) as potential agents for PNFs. Dinaciclib, a CDKi, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability, inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and CDK1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient-derived xenografts mouse models. Therefore, the combination of MEKi and CDKi may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant PNF patients.

2022-05-01 | GSE173577 | GEO

Impact of BRAF kinase inhibitors on miRNomes and transcriptomes of melanoma cells (gene expression dataset)

Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.

2017-03-06 | E-MTAB-5511 | biostudies-arrayexpress

Impact of BRAF kinase inhibitors on miRNomes and transcriptomes of melanoma cells (miRNA dataset)

2017-03-06 | E-MTAB-5510 | biostudies-arrayexpress

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