Melbourne Medical School Collected Works - Research Publications
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ItemMetabolic Plasticity in Melanoma Progression and Response to Oncogene Targeted Therapies(MDPI, 2021-11)Resistance to therapy continues to be a barrier to curative treatments in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Here, we discuss how the inherent metabolic plasticity of melanoma cells facilitates both disease progression and acquisition of anti-cancer therapy resistance. In particular, we discuss in detail the different metabolic changes that occur during the three major phases of the targeted therapy response-the early response, drug tolerance and acquired resistance. We also discuss how non-genetic programs, including transcription and translation, control this process. The prevalence and diverse array of these non-genetic resistance mechanisms poses a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes in the quest to prevent therapy resistance.
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ItemEnhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma(MDPI, 2021-12)Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
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ItemCDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway(MDPI, 2021-02)Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.
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ItemGenome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAFV600 melanoma cells(NATURE RESEARCH, 2020-10-12)Identification of mechanisms underlying sensitivity and response to targeted therapies, such as the BRAF inhibitor vemurafenib, is critical in order to improve efficacy of these therapies in the clinic and delay onset of resistance. Glycolysis has emerged as a key feature of the BRAF inhibitor response in melanoma cells, and importantly, the metabolic response to vemurafenib in melanoma patients can predict patient outcome. Here, we present a multiparameter genome-wide siRNA screening dataset of genes that when depleted improve the viability and glycolytic response to vemurafenib in BRAFV600 mutated melanoma cells. These datasets are suitable for analysis of genes involved in cell viability and glycolysis in steady state conditions and following treatment with vemurafenib, as well as computational approaches to identify gene regulatory networks that mediate response to BRAF inhibition in melanoma.
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ItemObesity and the Impact on Cutaneous Melanoma: Friend or Foe?(MDPI, 2020-06)Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favorable outcomes and this has been termed the "obesity paradox". In melanoma, the connection between obesity and the increased incidence is not as strong as for other cancer types with some but not all studies showing an association. However, several recent studies have indicated that increased body mass index (BMI) improves survival outcomes in targeted and immune therapy treated melanoma patients. The mechanisms underlying how obesity leads to changes in therapeutic outcomes are not completely understood. This review discusses the current evidence implicating obesity in melanoma progression and patient response to targeted and immunotherapy, and discusses potential mechanisms underpinning these associations.