Abstract
Although advances in targeted therapies have driven great progress in cancer treatment and outcomes, drug resistance remains a major obstacle to improving patient survival. Several mechanisms are involved in developing resistance to both conventional chemotherapy and molecularly targeted therapies, including drug efflux, secondary mutations, compensatory genetic alterations occurring upstream or downstream of a drug target, oncogenic bypass, drug activation and inactivation, and DNA damage repair. Extracellular vesicles (EVs) are membrane-bound lipid bilayer vesicles that are involved in cell–cell communication and regulating biological processes. EVs derived from cancer cells play critical roles in tumor progression, metastasis, and drug resistance by delivering protein and genetic material to cells of the tumor microenvironment. Understanding the biochemical and genetic mechanisms underlying drug resistance will aid in the development of new therapeutic strategies. Herein, we review the role of EVs as mediators of drug resistance in the context of cancer.
Highlights
Cancer is a major global public health issue and is the second leading cause of death worldwide
Upon the are formed through endosomal trafficking—a process in which exosomes form as intraluformation of exosomes, Rab-guanosine triphosphatases (Rab-GTPases) recruited to minal vesicles (ILVs) within multivesicular bodies (MVBs)
Combined treatment with vemurafenib and ALK inhibitors efficiently decreases tumor burden in mice bearing ALKpositive melanoma tumors [53]. These results demonstrate the importance of extracellular vesicles (EVs)-mediated protein transfer in mediating drug resistance in cells of the tumor microenvironment (TME)
Summary
Cancer is a major global public health issue and is the second leading cause of death worldwide. The development of resistance to therapeutic options—including both chemotherapy and targeted therapies—constitutes a fundamental challenge in cancer treatment which leads to treatment failure in over 90% of patients with metastatis disease [3]. Drug resistance involves a reduction in potency and efficacy of a drug and can lead to failure in achieving therapeutic goals, which in turn drives decreased survival. It can exist before the use of a therapeutic agent (intrinsic resistance) or can arise during treatment (acquired resistance) [4]. Recent research suggests a key role for extracellular vesicles (EVs), small membrane-bound vesicles that transfer cargo molecules amongst cells of the tumor and tumor microenvironment, in regulating the development of drug resistance (Figure 1). Out of cancer cells, inducing anti-apoptotic signals, modulating DNA repair, or mediating epithelial mesenchymal damage repair, or mediating epithelial to mesenchymal transition
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