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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations
Nourah Mohammad Obaid1, Karen Bedard2, Weei-Yuarn Huang3,4
1Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada. nourah-m-obaid@Dal.Ca.
Abstract:
The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance.
Insights
Targeted cancer therapies face resistance due to BRAF mutations. Combination therapies show promise but resistance persists, necessitating new strategies to overcome treatment challenges.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Resistance to targeted cancer therapies is a significant clinical challenge, particularly for tumors with the BRAF V600E mutation.
- Small molecule inhibitors targeting BRAFV600E have been developed, but intrinsic and acquired resistance remain problematic.
- Combination therapies, including BRAF and MEK inhibitors, improve outcomes but do not fully resolve resistance issues.
Purpose of the Study:
- To review mechanisms of resistance to BRAF-targeted therapies.
- To compare resistance patterns in melanoma and colorectal cancers.
- To discuss emerging strategies for overcoming treatment resistance.
Main Methods:
- Literature review of recent research articles on BRAF inhibitor resistance.
- Comparative analysis of resistance mechanisms in melanoma versus colorectal cancer.
- Exploration of proposed strategies to manage or prevent resistance.
Main Results:
- Acquired resistance to BRAF inhibitors is a common issue, even with combination therapies.
- Understanding resistance mechanisms is key to developing more effective treatments.
- Specific resistance mechanisms may differ between cancer types like melanoma and colorectal cancer.
Conclusions:
- Despite advances, resistance to BRAF-targeted therapies remains a critical concern.
- Further research into resistance mechanisms is essential for developing next-generation treatments.
- Novel strategies are needed to effectively manage and overcome acquired resistance in BRAF-mutated cancers.
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