Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors

Abstract

Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and severe toxicities; thus, novel therapeutic approaches are required to potentiate their efficacy and overcome drug resistance. In the last 20 years, the deregulation of epigenetic mechanisms has been shown to contribute to cancer hallmarks. Histone modifications play an important role in directing the transcriptional machinery and therefore represent interesting druggable targets. In this review, we focused on histone deacetylase inhibitors (HDACis) that can increase antitumor efficacy and overcome resistance to fluoropyrimidines by targeting specific genes or proteins. Our preclinical data showed a strong synergistic interaction between HDACi and fluoropyrimidines in different cancer models, but the clinical studies did not seem to confirm these observations. Most likely, the introduction of increasingly complex preclinical models, both in vitro and in vivo, cannot recapitulate human complexity; however, our analysis of clinical studies revealed that most of them were designed without a mechanistic approach and, importantly, without careful patient selection.

Keywords: HDAC inhibitors; drug resistance; fluoropyrimidines.

Figure 1

Classification of HDAC, their cellular localization and their inhibitors (HDACis). According to their structure and function, HDAC proteins are grouped into four classes. Class III deacetylases, sirtuins proteins, are not depicted here.

Figure 2

Mechanisms of the anticancer effects of HDAC inhibitors. HDAC inhibitors induced a pleiotropic effect on cancer cells, including modulation of survival pathways, angiogenesis, immune response, stemness, noncoding RNA, autophagy, DNA repair, DNA replication, apoptosis, cell cycle arrest, and oxidative stress.

Figure 3

Schematic representation of fluoropyrimidine metabolism.

Figure 4

Mechanisms of overcoming fluoropyrimidines drug resistance by HDACis. Red arrow connects the mechanisms by which cancer cells acquire resistance to fluoropyrimidines, whereas green arrow indicates that the treatment with HDACis could act on these mechanisms reverting the resistance and sensitizing cancer cells to chemotherapy treatment.