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Advancements in gene therapies targeting mutant KRAS in cancers
Yuhang Wang1, Thuy Anh Bui1,2,3, Xinpu Yang1
1School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Abstract:
Mutations in the KRAS gene are well-known tumourigenic drivers of colorectal, pancreatic and lung cancers. Mechanistically, these mutations promote uncontrolled cell proliferation and alter the tumour microenvironment during early carcinoma stages. Given their critical carcinogenic functions, significant progress has been made in developing KRAS inhibitors for cancer treatment. However, clinical applications of these KRAS inhibitor compounds are limited to specific cancer types which carry the relevant KRAS mutations. Additionally, clinical findings have shown that these compounds can induce moderate to serious side effects. Therefore, new approaches have emerged focusing on the development of universal therapeutics capable of targeting a wider range of KRAS mutations, minimising toxicity and enhancing the therapeutic efficacy. This review aims to examine these therapeutic strategies in the context of cancer treatment. It firstly provides an overview of fundamental KRAS biology within the cell signalling landscape and how KRAS mutations are associated with cancer pathogenesis. Subsequently, it introduces the development of current KRAS inhibitors which target certain KRAS mutants in different types of cancer. It then explores the potential of gene therapy approaches, including siRNA, miRNA and CRISPR methodologies. Furthermore, it discusses the use of lipid-based nanocarriers to deliver gene cargos for targeting KRAS gene mutants. Finally, it provides the insights into the future prospects for combatting KRAS mutation-associated cancers.
Insights
New KRAS therapies aim for universal application against cancer. This review explores gene therapy and nanocarriers to target KRAS mutations, reduce side effects, and improve efficacy for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- KRAS gene mutations are key drivers in colorectal, pancreatic, and lung cancers, promoting uncontrolled cell growth.
- Current KRAS inhibitors are specific to certain mutations and can cause significant side effects.
- There is a need for universal therapeutics targeting a broader range of KRAS mutations with reduced toxicity.
Purpose of the Study:
- To review fundamental KRAS biology and its role in cancer pathogenesis.
- To examine current KRAS inhibitors and their limitations.
- To explore emerging therapeutic strategies including gene therapy and nanocarrier delivery systems for KRAS-targeted cancer treatment.
Main Methods:
- Review of existing literature on KRAS biology, cancer mutations, and therapeutic strategies.
- Analysis of current KRAS inhibitors and their clinical applications.
- Exploration of gene therapy techniques (siRNA, miRNA, CRISPR) and lipid-based nanocarriers for gene delivery.
Main Results:
- KRAS mutations are critical oncogenic drivers, but current treatments face limitations in specificity and side effects.
- Gene therapy approaches offer potential for broader targeting of KRAS mutations.
- Lipid-based nanocarriers show promise for efficient delivery of gene therapies against KRAS.
Conclusions:
- Emerging universal therapeutics targeting KRAS mutations are crucial for improving cancer treatment outcomes.
- Gene therapy combined with nanocarrier delivery presents a promising avenue for future KRAS-targeted cancer therapies.
- Further research into these novel approaches is essential to overcome current treatment challenges.
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