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Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.

ABSTRACT: Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma cell lines with different disease-relevant mutations, to predict responsiveness to MEK inhibitor trametinib. Supported by multivariate statistical analysis and multidimensional pattern recognition algorithms, the responsiveness of individual cell lines to trametinib could be predicted with high accuracy (83% correct predictions), independent of mutation status. We also successfully employed this approach to case specifically predict whether individual melanoma cell lines could be sensitised to trametinib. Our predictions identified that combining MEK inhibition with selective targeting of c-JUN and/or FAK, using siRNA-based depletion or pharmacological inhibitors, sensitised resistant cell lines and significantly enhanced treatment efficacy. Our study indicates that multiplex proteomic analyses coupled with pattern recognition approaches could assist in personalising trametinib-based treatment decisions in the future.

SUBMITTER: Rozanc J

PROVIDER: S-EPMC6748097 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.

Rožanc Jan J Sakellaropoulos Theodore T Antoranz Asier A Guttà Cristiano C Podder Biswajit B Vetma Vesna V Rufo Nicole N Agostinis Patrizia P Pliaka Vaia V Sauter Thomas T Kulms Dagmar D Rehm Markus M Alexopoulos Leonidas G LG

Cell death and differentiation 20181015 8

Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma ...[more]

PMID: 30323272

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Project description:Background: Melanoma is the most lethal, and one of the most aggressive forms of cutaneous malignancies, which poor response to treatment has always puzzled clinicians. As is known to all, aging and immune microenvironment are two crucial factors impacting melanoma biological progress through the tumor microenvironment (TME). However, reliable biomarkers for predicting melanoma prognosis based on aging and immune microenvironment and therapeutic efficacy of immune checkpoints remain to be determined. Methods: The aging-related genes (ARGs) were obtained from the Human Ageing Genomic Resources and immune-related genes (IRGs) were downloaded from the Immunology database as well as Analysis Portal (ImmPort) database. Next, we initially performed LASSO regression and multivariate Cox regression to identify prognostic ARGs and IRGs in the TCGA and GSE65904 datasets, and firstly constructed a novel comprehensive index of aging and immune (CIAI) signature. Finally, in vitro molecular biology experiments were performed to assess the regulatory role of CNTFR in melanoma cell lines proliferation and migration, macrophage recruitment, and M2 polarization. Results: This novel CIAI signature consisted of 7 genes, including FOXM1, TP63, ARNTL, KIR2DL4, CCL8, SEMA6A, and CNTFR, in which melanoma patients in the high-CIAI group had shorter OS, DSS, and PFI, indicating CIAI model served as an independent prognostic index. Moreover, we found the CIAI score was potentially correlated with immune scores, estimate score, immune cell infiltration level, tumor microenvironment, immunotherapy effect, and drug sensitivity. Finally, CNTFR might function as oncogenes in melanoma cell lines and the silencing of CNTFR reduced macrophage recruitment and M2 polarization. Conclusion: In this study, we have first presented a novel prognostic CIAI model applied to assess immune checkpoint therapy and the efficacy of conventional chemotherapy agents in melanoma patients. Thus providing a new insight for combating melanoma.

Project description:Background. Consensus on standardized active surveillance or follow-up care by clinicians is lacking leading to considerable variation in practice across countries. An important structural modelling consideration is that self-examination by patients and their partners can detect melanoma recurrence outside of active surveillance regimes. Objectives. To identify candidate melanoma surveillance strategies for American Joint Committee on Cancer (AJCC) stage I disease and compare them with the current recommended practice in a cost-utility analysis framework. Methods. In consultation with UK clinical experts, a microsimulation model was built in TreeAge Pro 2019 R1.0 (Williamstown, MA, USA) to evaluate surveillance strategies for AJCC stage IA and IB melanoma patients separately. The model incorporated patient behaviors such as self-detection and emergency visits to examine suspicious lesions. A National Health Service (NHS) perspective was taken. Model input parameters were taken from the literature and where data were not available, local expert opinion was sought. Probabilistic sensitivity analysis, one-way sensitivity analysis on pertinent parameters and value of information was performed. Results. In the base-case probabilistic sensitivity analysis, less intensive surveillance strategies for AJCC stage IA and IB had lower total lifetime costs than the current National Institute for Health and Care Excellence (NICE) recommended strategy with similar effectiveness in terms of quality-adjusted life years and thereby likely to be cost-effective. Many strategies had similar effectiveness due to the relatively low chance of recurrence and the high rate of self-detection. Sensitivity and scenario analyses did not change these findings. Conclusions. Our model findings suggest that less resource intensive surveillance may be cost-effective compared with the current NICE surveillance guidelines. However, to advocate convincingly for changes, better evidence is required.

Project description:Background:Despite the progress made in the clinical management of metastatic melanoma, a patient's response to treatment cannot be fully predicted, and intrinsic or acquired resistance that is developed in most melanoma patients warrants further research efforts. In addition to genetic factors, microenvironmental input should be considered to explain the diversity of response to treatment among melanoma patients. In this study, we evaluated the impact of insulin on patient-derived BRAFV600E melanoma cells, either untreated or treated with vemurafenib or trametinib, inhibitors of BRAFV600 and MEK1/2, respectively. Methods:Cells were cultured in serum-free conditions, either with or without insulin. The activity of the MAPK/ERK and PI3K/AKT pathways was assessed by Western blotting, cell viability, and percentages of Ki-67- and NGFR-positive cells by flow cytometry. Transcript levels were analyzed using qRT-PCR, and ?-H2AX levels by immunoblotting and confocal microscopy. A luminescence-based assay was used to measure glutathione content. Results:While insulin did not influence the MAPK/ERK pathway activity, it had a strong influence on melanoma cells, in which this pathway was suppressed by either vemurafenib or trametinib. In the presence of insulin, both drugs were much less efficient in 1) inhibiting proliferation and reducing the percentage of Ki-67-positive cells, and 2) inducing apoptosis and phosphorylation of histone H2AX in melanoma cells. Changes induced by vemurafenib and trametinib in glutathione homeostasis and DNA repair gene expression were also attenuated by insulin. Moreover, insulin impaired the combined effects of targeted drugs and doxorubicin in melanoma cells. In addition to insulin-induced PI3K/AKT activity, which was either transient or sustainable depending on the cell line, an insulin-triggered increase in the percentage of cells expressing NGFR, a marker of neural crest stem-like cells, may contribute to the reduced drug efficacy. Conclusion:Our results demonstrate the role of insulin in reducing the efficacy of vemurafenib and trametinib. This needs clinical assessment.

Dataset Information

Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.

Publications

Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.

Similar Datasets

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