Overcoming therapeutic resistance to platinum-based drugs by targeting Epithelial-Mesenchymal transition

Abstract

Platinum-based drugs (PBDs), including cisplatin, carboplatin, and oxaliplatin, have been widely used in clinical practice as mainstay treatments for various types of cancer. Although there is firm evidence of notable achievements with PBDs in the management of cancers, the acquisition of resistance to these agents is still a major challenge to efforts at cure. The introduction of the epithelial-mesenchymal transition (EMT) concept, a critical process during embryonic morphogenesis and carcinoma progression, has offered a mechanistic explanation for the phenotypic switch of cancer cells upon PBD exposure. Accumulating evidence has suggested that carcinoma cells can enter a resistant state via induction of the EMT. In this review, we discussed the underlying mechanism of PBD-induced EMT and the current understanding of its role in cancer drug resistance, with emphasis on how this novel knowledge can be exploited to overcome PBD resistance via EMT-targeted compounds, especially those under clinical trials.

Keywords: cancer stem cells; drug resistance; epithelial-mesenchymal transition; platinum-based drugs; targeted therapy.

Figure 1

EMT-related principles underlying cancer drug resistance. The epithelial-mesenchymal transition (EMT) is a dynamic process that consists of three states: an epithelial state with epithelial phenotypes, a hybrid state with epithelial phenotypes and mesenchymal phenotypes, and a mesenchymal state with mesenchymal phenotypes. In the latter two states, a small number of cancer stem cells and drug-tolerant persister cells occur to inhibit anticancer treatments.

Figure 2

Mechanisms involved in PBD-induced EMT. TGF-β interacts with TGF-β receptors (TGF-βr1/2) to induce phosphorylation of Smad2/3, which binds to Smad4 to form a Smad2/3/4 complex. After platinum-based drugs (PBDs) enter tumor cells, they bind to the N-terminus of β-catenin and upregulate BCL9. BCL9 can form a complex with β-catenin to create positive feedback that promotes β-catenin expression, and induces the epithelial-mesenchymal transition (EMT). The pathways for Notch1 to induce EMT include: promoting melanoma cell adhesion molecule (MCAM) expression and binding of the Notch1 internal domain (ICD) to the CBF1 site of the major vault protein (MVP) gene to upregulate MVP. The binding of tumor necrosis factor (TNF) to membrane surface receptors drives IkB kinase (IKK) to phosphorylate IkB. Degradation of IkB forms the p65/p50 dimeric complex that binds to EMT-related genes.

Figure 3

PBDs induce drug resistance through EMT in cancer cells. Platinum-based drugs can induce EMT through multiple sites/pathways and are either fully or partially transformed. In addition to the mesenchymal-like phenotype of tumor cells, a small number of other phenotypes appear during this process. Other cell types include persistent drug-resistant cells, cancer stem cells, and circulating tumor cells. These EMT-related cells can evade the deadly effect of PBDs, migrate to distant tissues and organs via the blood circulation and other routes, and cause in situ tumor relapse and metastatic foci after stopping medication.

Figure 4

Illustration representing several anti-EMT therapies to overcome drug resistance. In clinical applications, platinum-based drugs can cause the induction and development of EMT by activating EMT-related signals, regulating circadian rhythms, regulating epigenetics, causing hypoxia, inducing autophagy, and stimulating exosome secretion, thereby generating tumor cells’ resistance to PBDs. Use of modality-related inhibitors can prevent and reverse EMT, enhancing the efficacy of PBDs. In addition, some small molecules can target EMT cells and prevent them from entering a drug-resistant state.