Drug resistance of BRAF-mutant melanoma: Review of up-to-date mechanisms of action and promising targeted agents

Rossi, Alessandro; Roberto, Michela; Panebianco, Martina; Botticelli, Andrea; Mazzuca, Federica; Marchetti, Paolo

doi:10.1016/j.ejphar.2019.172621

Cited by 66 publications

(72 citation statements)

References 150 publications

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“…These mechanisms include a.o. genetic causes, epigenomic and transcriptomic changes, altered communication with the tumor microenvironment, an immunomodulatory effect, and the presence of CSCs [17]. Genetic mechanisms of resistance apply to BRAF alone: amplification of gene copying and alternative splicing, which were detected in 20%-32% of melanoma cases [18,19], or genes encoding proteins directly, and indirectly interacting with BRAF kinase.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of epigenomic or transcriptomic changes, which constitute ca. 40% of cases with identified BRAF mutation and treated with a specific inhibitor, many aberrations are present in elements of negative feedback loops regulating MAPK and PI3K/AKT pathways [17,21]. A great number of changes directly involve elements of the MAPK pathway-there is evidence of hyperactivation and overexpression of RAS or RTKs, e.g., IGFR1, PDGFRβ, EGFR [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…In the literature, many promising therapies that are able to overcome drug resistance in mutant BRAF melanoma cells can be found. Aside from the most common treatment combining BRAF and MEK inhibitors (reviewed in [17]), there is a trend to look into drugs targeting other molecules involved in resistance mechanisms. Taking into account the overexpression and increased activation of RTKs in generated resistant cells, priming these molecules as potential therapy targets, we tested the efficiency of combination treatment using inhibitors of EGFR (lapatinib) and MET (foretinib) in this model.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Dratkiewicz

Simiczyjew

Pietraszek-Gremplewicz

et al. 2019

IJMS

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Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of inhibitors directed against EGFR (epidermal growth factor receptor) and MET (hepatocyte growth factor receptor) trigger a synergistic cytotoxic effect in human melanoma cells, and decrease their invasive abilities. In this study, we aimed to generate and characterize melanoma cells resistant to vemurafenib treatment, and then to evaluate the effectiveness of a previously developed therapy in this model. We showed that melanoma cells resistant to the BRAF inhibitor are characterized by a lower proliferation rate and they acquire a spindle-like shape. Using Western Blot, we also noticed increased levels of EGFR, MET, and selected markers of cancer stem cells in generated cell lines. Resistant cells also exhibited increased invasive abilities and elevated proteolytic activity, observed using scratch wound assays and gelatin zymography. Moreover, combination therapy reduced their viability, as measured with a colorimetric cytotoxicity test, and decreased invasiveness. The obtained results validate the application of combination therapy directed against EGFR and MET in melanoma cells resistant to treatment with inhibitors of mutated BRAF.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Dratkiewicz

Simiczyjew

Pietraszek-Gremplewicz

et al. 2019

IJMS

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“…We propose here a pipeline based 41 on logical modelling and able to go from the formulation of a biological question to the validation of 42 a mathematical model on pre-clinical data, in this case a set of cell lines (Fig 1), and the 43 subsequent interpretation of potential resistance mechanisms. The application of the mechanistic 44 model to different cell lines is therefore done without any training of parameters but only on the 45 basis of the automatic integration and interpretation of their omic features. The construction of a mathematical model must be based first and foremost on a precise and 48 specific biological problem, at the origin of the design of the model.…”

Section: Introductionmentioning

confidence: 99%

“…A generic logical model for melanoma and colorectal cancers 250 The construction of the logical model aims at summarizing the current molecular understanding of 251 BRAF gene and its molecular partners in both colorectal cancers and melanomas. The focus of this 252 model is put on two important signalling pathways involved in the mechanisms of resistance to 253 BRAF inhibition which are the ERK1/2 MAPK and PI3K/AKT pathways [44,45].…”

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confidence: 99%

Personalized logical models to investigate cancer response to BRAF treatments in melanomas and colorectal cancers

Béal

Pantolini

Noël

et al. 2020

Preprint

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The study of response to cancer treatments has benefited greatly from the contribution of different omics data but their interpretation is sometimes difficult. Some mathematical models based on prior biological knowledge of signalling pathways, facilitate this interpretation but often require fitting of their parameters using perturbation data. We propose a more qualitative mechanistic approach, based on logical formalism and on the sole mapping and interpretation of omics data, and able to recover differences in sensitivity to gene inhibition without model training. This approach is showcased by the study of BRAF inhibition in patients with melanomas and colorectal cancers who experience significant differences in sensitivity despite similar omics profiles.We first gather information from literature and build a logical model summarizing the regulatory network of the mitogen-activated protein kinase (MAPK) pathway surrounding BRAF, with factors involved in the BRAF inhibition resistance mechanisms. The relevance of this model is verified by automatically assessing that it qualitatively reproduces response or resistance behaviours identified in the literature. Data from over 100 melanoma and colorectal cancer cell lines are then used to validate the model's ability to explain differences in sensitivity. This generic model is transformed into personalized cell line-specific logical models by integrating the omics information of the cell lines as constraints of the model. The use of mutations alone allows personalized models to correlate significantly with experimental sensitivities to BRAF inhibition, both from drug and CRISPR targeting, and even better with the joint use of mutations and RNA, supporting multi-omics mechanistic models. A comparison of these untrained models with learning approaches highlights similarities in interpretation and complementarity depending on the size of the datasets.This parsimonious pipeline, which can easily be extended to other biological questions, makes it possible to explore the mechanistic causes of the response to treatment, on an individualized basis. Author summaryWe constructed a logical model to study, from a dynamical perspective, the differences between melanomas and colorectal cancers that share the same BRAF mutations but exhibit different sensitivities to anti-BRAF treatments. The model was built from the literature and completed from May 30, 2020 1/24 existing pathway databases. The model encompasses the key proteins of the MAPK pathway and was made specific to each cancer cell line (100 melanoma and colorectal cell lines from public database) using available omics data, including mutations and RNAseq data. It can simulate the effect of drugs and show high correlation with experimental results. Moreover, the structure of the network confirms both the importance of the reactivation of the MAPK pathway through CRAF and the involvement of PI3K/AKT pathway in the mechanisms of resistance to BRAF inhibition. The study shows that, because of the low number of samples, the ...

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Design and Synthesis of Novel 2‐Acetamido, 6‐Carboxamide Substituted Benzothiazoles as Potential BRAFV600E Inhibitors – In vitro Evaluation of their Antiproliferative Activity

Batsi,

Antonopoulou,

Fotopoulou

et al. 2023

ChemMedChem

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The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2‐acetamido‐1,3 benzothiazole‐6‐carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2‐acetamidobenzo[d]thiazole‐6‐carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position‐2 by an acetamido moiety and at position‐6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non‐aromatic) terminal pharmacophore in the order ‐C6H4‐NHSO2‐R or reversevely ‐C6H4‐SO2N(H)‐R. These analogs were subsequently biologically evaluated as potential BRAFV600E inhibitors and antiproliferative agents in several colorectal cancer and melanoma cell lines. In all assays applied, one analog, namely 2‐acetamido‐N‐[3‐(pyridin‐2‐ylamino)propyl]benzo[d]thiazole‐6‐carboxamide (22), provided promising results in view of its use in drug development.

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Drug resistance of BRAF-mutant melanoma: Review of up-to-date mechanisms of action and promising targeted agents

Cited by 66 publications

References 150 publications

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Personalized logical models to investigate cancer response to BRAF treatments in melanomas and colorectal cancers

Design and Synthesis of Novel 2‐Acetamido, 6‐Carboxamide Substituted Benzothiazoles as Potential BRAFV600E Inhibitors – In vitro Evaluation of their Antiproliferative Activity

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