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Combinatorial treatment with PARP and MAPK inhibitors overcomes phenotype switch-driven drug resistance in advanced melanoma

ABSTRACT: Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors. A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of melanoma patients. Using a drug screen targeting chromatin regulators in patient-derived 3D MAPK inhibitor-resistant melanoma cell cultures, we discovered that PARP inhibitors restore sensitivity to MAPK inhibitors, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARP inhibitors induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed EMT-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPK inhibitor-sensitive state. The combination of PARP and MAPK inhibitors synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating melanoma patients with PARP inhibitors in combination with MAPK inhibitors to abrogate acquired therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221241 | GEO | 2023/08/24

REPOSITORIES: GEO

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Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma

Project description:Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted drugs such as MAPK inhibitors (MAPKi). Here, using a drug screen targeting chromatin regulators in patient-derived 3D melanoma cell cultures, we discovered that PARP inhibitors are capable of restoring MAPKi sensitivity. This synergy was found to be independent of DNA damage repair pathways and was effective both in vitro and in vivo in patients-derived xenografts. Strikingly, through integrated transcriptomic, proteomic and epigenomic analysis, we discovered that PARPi induces lysosomal autophagy which was accompanied by enhanced mitochondrial lipid metabolism that, ultimately, increased antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, we also found that PARP inhibitors regulated EMT-like phenotype switching by dampening the mesenchymal phenotype via transcriptomic and epigenetic rearrangements. This, in turn, redirected melanoma cells towards a proliferative and, thus, MAPKi-sensitive state. Our study provides a scientific rational for treating patients with PARPi in combination with MAPKi to annihilate acquired therapy resistance.

2023-09-08 | PXD038822 | Pride

Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma

Project description:The prognosis for most patients with advanced malignant melanoma is traditionally very poor, as the disease is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments. Here, using a drug screen targeting chromatin regulators in patient-derived 3D melanoma cell cultures, we discovered that PARP inhibitors are capable of restoring MAPKi sensitivity. This synergy was found to be independent of DNA damage repair pathways and was effective both in vitro and in vivo in patients-derived xenografts. Strikingly, through integrated transcriptomic, proteomic and epigenomic analysis, we discovered that PARPi induces lysosomal autophagy which was accompanied by enhanced mitochondrial lipid metabolism that, ultimately, increased antigen presentation and T-cell cytotoxicity. Moreover, we also found that PARP inhibitors regulated EMT-like phenotype switching by dampening the mesenchymal phenotype via transcriptomic and epigenetic rearrangements. This, in turn, redirected melanoma cells towards a proliferative and, thus, MAPKi-sensitive state. Our study provides a scientific rational for treating patients with PARPi in combination with MAPKi to annihilate acquired therapy resistance

2023-07-01 | GSE221233 | GEO

RNA-seq of human melanoma cell line A375m2 treated with SB202190 OR BIRB796 against DMSO-treated controls

Project description:Melanoma cells can switch between a more differentiated, proliferative phenotype and a dedifferentiated, invasive phenotype in response to signals from the environment. We found that p38 MAPK inhibitors SB202190 and BIRB796 induce phenotype switching from the dedifferentiated, invasive phenotype to the more differentiated phenotype in A375m2 melanoma cells cultured in three-dimensional collagen. The phenotype switch is accompanied by a morphological transition from rounded, blebby, amoeboid shape to elongated, spindle-like morphology. We performed transcriptome profiling with RNA-seq to uncover the underlying gene expression changes. Cells kept in 3D collagen were treated either with 10 µM inhibitor or with 0.1% DMSO (the vehicle) only for 48 hours and total RNA was isolated using a TRIzol-like procedure. Sequencing libraries were prepared from poly(A) RNA and sequenced with Illumina HiSeq 2500 instrument.

2020-11-28 | E-MTAB-9273 | biostudies-arrayexpress

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma [ChIP-seq]

Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.

2024-02-22 | GSE254701 | GEO

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

2024-02-01 | GSE156250 | GEO

Proteomic analysis of melanoma resistant cells transfected with siRNA targeting DDR2 or treated with DDR2 inhibitor or Dasatinib

Project description:Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In 70% of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.

2023-05-02 | PXD028292 | Pride

Proteogenomics analysis to identify acquired resistance-specific alterations in melanoma PDXs on MAPKi therapy

Project description:Therapeutic approaches to treat melanoma include small molecule drugs that target activating protein mutations in pro-growth signaling pathways like the MAPK pathway. While beneficial to the approximately 50% of patients with activating BRAFV600 mutation, mono- and combination therapy with MAPK inhibitors is ultimately associated with acquired resistance. To better characterize the mechanisms of MAPK inhibitor resistance in melanoma, we utilize patient-derived xenografts and apply proteogenomic approaches leveraging genomic, transcriptomic, and proteomic technologies that permit the identification of resistance-specific alterations and therapeutic vulnerabilities. A specific challenge for proteogenomic applications comes at the level of data curation to enable multi-omics data integration. Here, we present a proteogenomic approach that uses custom curated databases to identify unique resistance-specific alternations in melanoma PDX models of acquired MAPK inhibitor resistance. We demonstrate this approach with a NRASQ61L melanoma PDX model from which resistant tumors were developed following treatment with a MEK inhibitor. Our multi-omics strategy addresses current challenges in bioinformatics by leveraging development of custom curated proteogenomics databases derived from individual resistant melanoma that evolves following MEK inhibitor treatment and is scalable to comprehensively characterize acquired MAPK inhibitor resistance across patient-specific models and genomic subtypes of melanoma.

2024-01-24 | MSV000093912 | MassIVE

Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ and Wnt/β-catenin signaling in melanoma phenotype switching

Project description:In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFb/SMAD, Hippo/YAP/TAZ and Wnt/b-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFb/SMAD, YAP/TAZ and b-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of b-catenin, with YAP/TAZ governing an essential sub-program of TGFb-induced phenotype switching. Wnt/b-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ-induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

2021-11-11 | GSE188463 | GEO

Predominance of MAPK reactivation in early resistance to debrafenib/trametinib combination therapy of BRAF mutant metastatic melanoma.

Project description:One third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within six months. Treatment options for these patients remain limited. Here we analyse twenty BRAFV600 mutant melanoma metastases derived from 10 patients treated with the combination of debrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumors and MAPK reactivation occurred in 9/10 tumors, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein confers resistance to combination therapy, highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (e.g. RCA1 and AKT3) that activate the MAPK and P13K pathways and are thus predicted to diminish response to MAPK inhibitors. Total RNA obtained from fresh frozen melanoma tumors treated with a combination of dabrafenib and trametinib

2014-12-03 | E-GEOD-61992 | biostudies-arrayexpress

SOX-2 mediated upregulation of CD24 promotes adaptive resistance towards targeted therapy in melanoma

Project description:Melanoma is one of the most aggressive types of skin cancer and is often characterized by a constitutively activate RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the underlying mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that in targeted therapy resistant, melanoma-derived induced pluripotent cancer cells (iPCCs) SOX2 and CD24 are upregulated. It is known that both SOX2 and CD24 expression promote an undifferentiated and cancer stem cell like phenotype, which is associated with higher therapy resistance. We therefore elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment and that SOX2 is able to upregulate the expression of CD24 by binding to the CD24 promoter. Furthermore, we show that SOX2 or CD24 overexpression significantly increase the resistance towards BRAF inhibitors, while SOX2 knock-down rendered cell sensitive towards treatment. Moreover, CD24 and SOX2 are able to upregulate Src and STAT3 activity which could contribute to the increased resistance. Importantly, CD24 knockdown or Src inhibition in resistant SOX2 overexpressing cells, the sensitivity towards BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the upregulation of CD24 by SOX2 resulting in increased activity of Scr and STAT3. Thus, to prevent adaptive resistance it might be beneficial to use Src or STAT3 inhibitors together with MAPK pathway inhibitors.

2018-05-15 | GSE106321 | GEO

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