Abstract
Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage differentiation potential, are known to be intrinsically resistant to anticancer treatments. In this review, we analyzed the implications for CSCs in drug resistance and described that multiple alterations in morphogenetic pathways (i.e., Hippo, Wnt, JAK/STAT, TGF-β, Notch, Hedgehog pathways) were suggested to be critical for CSC plasticity. By interrogating The Cancer Genome Atlas (TCGA) datasets, we first analyzed the prevalence of morphogenetic pathways alterations in solid tumors with associated outcomes. Then, by highlighting epigenetic relevance in CSC development and maintenance, we selected histone deacetylase inhibitors (HDACi) as potential agents of interest to target this subpopulation based on the pleiotropic effects exerted specifically on altered morphogenetic pathways. In detail, we highlighted the role of HDACi in solid cancers and, specifically, in the CSC subpopulation and we pointed out some mechanisms by which HDACi are able to overcome drug resistance and to modulate stemness. Although, further clinical and preclinical investigations should be conducted to disclose the unclear mechanisms by which HDACi modulate several signaling pathways in different tumors. To date, several lines of evidence support the testing of novel combinatorial therapeutic strategies based on the combination of drugs commonly used in clinical practice and HDACi to improve therapeutic efficacy in solid cancer patients.
Highlights
Drug resistance is a well-known phenomenon that arises when a disease becomes tolerant to treatment
We demonstrated that histone deacetylases (HDAC) inhibitors (HDACi), such as vorinostat and valproic acid (VPA), were able to induce selective death of the Cancer stem cells (CSCs) subpopulation in non-small-cell lung cancer (NSCLC)
We emphasized the aspects related to CSCs and their involvement in this phenomenon, reviewing what is known in the literature
Summary
Drug resistance is a well-known phenomenon that arises when a disease becomes tolerant to treatment. They conclude that HDACi reduce mortality in experimental models by conferring multi-organ protection, often following a single treatment administered in some cases post injury, suggesting the design of early phase clinical trials in order to confirm the protective role exerted by these agents [22] From this perspective, the increased dependency of tumor cells on HDACs and their upregulation during transformation could help identifying the therapeutic window’s width of HDACi. At the same time, we should be aware of the potential toxicity induced by this class of agent. Considering all intrinsic and extrinsic features of CSCs responsible for chemo-toxicity escape, we discuss the capability of HDACi, alone or in combination, to overcome chemo-resistance
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