Cell signaling and cancer: a mechanistic insight into drug resistance

Abstract

Drug resistance is a major setback for advanced therapeutics in multiple cancers. The increasing prevalence of this resistance is a growing concern and bitter headache for the researchers since a decade. Hence, it is essential to revalidate the existing strategies available for cancer treatment and to look after a novel therapeutic approach for target based killing of cancer cells at the genetic level. This review outlines the different mechanisms enabling resistance including drug efflux, drug target alternation, alternative splicing, the release of the extracellular vesicle, tumor heterogeneity, epithelial-mesenchymal transition, tumor microenvironment, the secondary mutation in the receptor, epigenetic alternation, heterodimerization of receptors, amplification of target and amplification of components rather than the target. Furthermore, existing evidence and the role of various signaling pathways like EGFR, Ras, PI3K/Akt, Wnt, Notch, TGF-β, Integrin-ECM signaling in drug resistance are explained. Lastly, the prevention of this resistance by a contemporary therapeutic strategy, i.e., a combination of specific signaling pathway inhibitors and the cocktail of a cancer drug is summarized showing the new treatment strategies.

Keywords: Aberrant signaling; Cancer; Cross-resistance; Drug resistance; Therapeutics.