Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

Tolcher, Anthony W.; Wei, Peng; Calvo, Emiliano

doi:10.1158/1535-7163.mct-17-0349

Cited by 81 publications

(71 citation statements)

References 109 publications

(120 reference statements)

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“…Furthermore, we identified two cases with BRAF mutations of which one (sample AEM-1) exhibited a hotspot V600E variant. To our knowledge, BRAF has not been reported to be altered in BAC before but could represent an important drug target [35]. A key observation of Roy et al was the absence of any SNV or CNA in BAC with mucinous histology [9]; however, both analysed mucinous BAC cases in our cohort exhibited several mutations in KRAS, TP53 and ARID1A, SMAD4, TP53, respectively.…”

Section: Discussionmentioning

confidence: 51%

Comparative genomic profiling of glandular bladder tumours

et al. 2020

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Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.

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Section: Discussionmentioning

confidence: 51%

Comparative genomic profiling of glandular bladder tumours

et al. 2020

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“…RAF and MEK inhibitors are usually described as being synergistic with respect to their effects on MAPK activity in patients (Tolcher et al, 2018), however their differential potency on oncogenic and RTK-mediated signaling suggests a more complex reality. In particular, experiments and modelling suggest that RAF and MEK inhibitors are poor inhibitors of RTK-mediated signaling.…”

Section: Combined Raf and Mek Inhibition Fails To Suppress Receptor-dmentioning

confidence: 99%

Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAF^V600Emelanoma cells

Gerosa

Chidley

Froehlich

et al. 2019

Preprint

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Anti-cancer drugs commonly target signal transduction proteins activated by mutation. In patients with BRAF V600E melanoma, small molecule RAF and MEK kinase inhibitors cause dramatic but often transient tumor regression. Emerging evidence suggests that cancer cells adapting by non-genetic mechanisms constitute a reservoir for the development of drug-resistant tumors. Here, we show that few hours after exposure to RAF/MEK inhibitors, BRAF V600E melanomas undergo adaptive changes involving disruption of negative feedback and sporadic pulsatile reactivation of the MAPK pathway, so that MAPK activity is transiently high enough in some cells to drive proliferation. Quantitative proteomics and computational modeling show that pulsatile MAPK reactivation is possible due to the co-existence in cells of two MAPK cascades: one driven by BRAF V600E that is drug-sensitive and a second driven by receptors that is drug-resistant. Paradoxically, this may account both for the frequent emergence of drug resistance and for the tolerability of RAF/MEK therapy in patients.

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“…HDAC inhibitors were shown to sensitize melanoma cells to BRAF/MEK inhibitors (Maertens et al, 2019). These examples of therapeutic combinations could be further extended using efficient miniaturized platforms able to support the high throughput micro-screening of compounds on biopsies or circulating tumor cells (Tolcher et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Functionalized Graphene Oxide Thin Films for Anti-tumor Drug Delivery to Melanoma Cells

Sima

Chirițoiu²,

Neguț³

et al. 2020

Front. Chem.

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Since Graphene discovery, their associated derivate nanomaterials, Graphene Oxide (GO) and reduced-GO were in the forefront of continuous developments in bio-nano-technology due to unique physical-chemical properties. Although GO nano-colloids (GON) were proposed as drug release matrix for targeting cancer cells, there is still a concern regarding its cytotoxicity issues. In this study, we report on the fabrication of functional GON bio-coatings by Matrix-Assisted Pulsed Laser Evaporation (MAPLE) to be used as drug carriers for targeting melanoma cells. We first performed a thorough in vitro cytotoxicity assay for comparison between GON and protein functionalized GON coatings. As functionalization protein, Bovine Serum Albumin (BSA) was non-covalently conjugated to GO surface. Safe concentration windows were identified in cytotoxicity tests by live/dead staining and MTS assays for five different human melanoma cell lines as well as for non-transformed melanocytes and human dermal fibroblasts. Hybrid GON-BSA nano-scaled thin coatings incorporating Dabrafenib (DAB) and Trichostatin A (TSA) inhibitors for cells bearing BRAF V600E pathway activating mutation were assembled on solid substrates by MAPLE technique. We further demonstrated the successful immobilization for each drug-containing GON-BSA assembling systems by evaluating cellular BRAF activity inhibition and histone deacetylases activity blocking, respectively. DAB activity was proven by the decreased ERK phosphorylation in primary melanoma cells (SKmel28 BRAF V600E cell line), while TSA effect was evidenced by acetylated histones accumulation in cell's nuclei (SKmel23 BRAF WT cell line). In addition, melanoma cells exposed to GON-BSA coatings with compositional gradient of inhibitors evidenced a dose-dependent effect on target activity. Such functional bio-platforms could present high potential for cell-biomaterial interface engineering to be applied in personalized cancer therapy studies.

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Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

Abstract: Molecular characterization of oncogenic mutations within genes in the MAPK and

Cited by 81 publications

References 109 publications

Comparative genomic profiling of glandular bladder tumours

Comparative genomic profiling of glandular bladder tumours

Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAF^V600Emelanoma cells

Functionalized Graphene Oxide Thin Films for Anti-tumor Drug Delivery to Melanoma Cells

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Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

Abstract: Molecular characterization of oncogenic mutations within genes in the MAPK and

Cited by 81 publications

References 109 publications

Comparative genomic profiling of glandular bladder tumours

Comparative genomic profiling of glandular bladder tumours

Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAFV600Emelanoma cells

Functionalized Graphene Oxide Thin Films for Anti-tumor Drug Delivery to Melanoma Cells

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Product

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Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAF^V600Emelanoma cells