Advancements in gene therapies targeting mutant KRAS in cancers.

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.