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Small molecule inhibitors in melanoma Kenski Kong WES

ABSTRACT: Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15–20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients.

PROVIDER: EGAS00001002863 | EGA |

REPOSITORIES: EGA

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EGAS00001002863-sc-2019-04-11T08:44:10Z - samples

Project description:Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15-20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients. . This dataset contains all the data available for this study on 2019-04-11.

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Project description:BRAF, one of three RAF serine/threonine kinases (ARAF, BRAF and CRAF), plays a major role in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway, which mediates cellular responses to growth signals. Recently a high frequency (~60%-70%) of activating BRAF mutations (predominantly V600E) has been reported in malignant melanoma. In order to identify the downstream effects of BRAF signaling on melanoma cell growth and gene expression, cDNA microarray analysis was carried out following BRAF siRNA or MEK1/2 inhibitor (U0126) treatment. Keywords: time series, siRNA time series, siRNA, drug treatment

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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.

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Anti-proliferative effects of continued mitogen activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma: Implications for treatment beyond disease progression

Project description:Inhibitors of the MAPKs, BRAF and MEK, induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6-7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now demonstrate that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signalling, decrease in BrdU incorporation and S-phase inhibition. This cytostatic effect was also associated diminished levels of cyclin D1 and p-pRb.. Two short-term melanoma cultures generated from resistant tumour biopsies also responded to MAPK inhibition with comparable inhibitory changes in proliferation and MAPK signalling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Total RNA obtained from melanooma cell lines treated for 24h with dabrafenib, trametinib or combination of dabrafenib and trametinib

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RNAseq changes in mouse wound with or without time course treatment by Vemurafenib

Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14

2016-07-29 | E-GEOD-74558 | biostudies-arrayexpress

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

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Project description:Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n=26), or durvalumab and trametinib given concomitantly (cohort B, n=20) or sequentially (cohort C, n=22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.

2020-09-24 | GSE158403 | GEO

DNA Seq data: biopy samples from patients pre- and post- treated with Vorinostat

Project description:BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. DNA Seq data: biopy samples from patients pre- and post- treated with Vorinostat; check mutations related to MAPKi-resistance

2018-04-18 | GSE111140 | GEO

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