Targeting the JNK-JUN pathway to reduce phenotypic plasticity and overcome therapy resistance in metastatic melanoma
Petranel Ferrao
Institute for Breathing and Sleep
Dr Ferrao has over 15 years of research, teaching and commercial experience in the biomedical sciences. With a passion for translational research she has led innovative research to novel discoveries that have contributed to the advancement of cancer treatments in clinical development. Building upon her training and expertise in Receptor Tyrosine kinases, signalling and drug resistance, she focuses on two main areas: defining predictors of therapy response and investigating mechanisms of drug resistance to cancer treatments. She has a clear vision for contributing to precision medicine through innovative research by advancing the personalised use of current/new therapies for patient benefit.
Abstract
IntroductionPatients with metastatic melanoma have displayed remarkable responses to targeted and immune therapies that have been approved for treatment in recent years. However, responses to targeted therapies are partial or... [ view full abstract ]
Introduction
Patients with metastatic melanoma have displayed remarkable responses to targeted and immune therapies that have been approved for treatment in recent years. However, responses to targeted therapies are partial or short-lived in the majority of patients, and responses to immune modulating therapies are limited to a small proportion of patients. Combination treatments with therapies that are able to overcome the inherent and early adaptive resistance mechanisms will provide more durable responses and survival benefits for melanoma patients.
Methods and Results
Pharmaco-genomic analysis identified activation of the JNK-JUN pathway as a key mechanism of cell survival, drug resistance and EMT-like phenotype-switching during early drug adaptation to treatment with BRAF/MEK/ERK inhibitors (1). Combination treatment with JNK inhibitors or siRNA-mediated reduction in c-JUN levels was sufficient to overcome inherent and early adaptive resistance to inhibition of the RAF-MEK-ERK pathway (1). Scheduling of JNK inhibitor combination after early adaptive changes that up-regulated c-JUN resulted in enhanced cell killing (1) There was a strong correlation in multiple melanoma microarray datasets between high JUN expression and a mesenchymal-like phenotype (1). A significant correlation was also detected between high JUN expression and high expression of CD274 encoding PD-L1 (2).
Discussion
Targeting the JNK-JUN pathway in melanoma offers the potential to overcome therapy resistance to RAF-MEK-ERK pathway targeted therapies, while simultaneously addressing phenotypic changes that have been linked to immune evasion and metastasis promoting properties (3). Hence, pre-clinical optimisation of drug candidates and scheduling of JNK-JUN pathway inhibitor treatments will be critical for exploiting the changes associated with phenotypic plasticity, to obtain more effective and durable responses to targeted and/or immune therapies in the treatment of melanoma.
1. R Ramsdale, R Jorissen, et .al ., P T Ferrao. (2015). Science Signaling 8: 390 ra82.
2. P T C Ferrao (2016) International (PCT) Patent Application No. PCT/AU/2016/050075 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123679
3. P T Ferrao. (2016) Molecular and Cellular Oncology. 3(3): e1128515.
Authors
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Petranel Ferrao
(Institute for Breathing and Sleep)
Topic Area
Drug target discovery and integration with individualized therapy, integration of diagnosi
Session
PS1 » Poster Session (14:00 - Monday, 25th June, Main hall)
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