Mechanisms of Resistance to Histone Deacetylase Inhibitors and Their Therapeutic Implications

Abstract

Histone deacetylase inhibitors (HDI) are a promising new approach to the treatment of cancer.HDIs have been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of transformed cell lines; inhibit tumor growth in animal models; and show antitumor activity in clinical trials.Vorinostat, which has shown clinical responses in f30% of patients with advanced cutaneousT-cell lymphoma, is the first HDI approved for the treatment of cancer, and it is currently being evaluated in other indications. A better understanding of the molecular determinants of resistance to HDIs may provide the basis for therapeutic combinations with improved clinical efficacy. Poor response to treatment could be linked to systemic factors like pharmacokinetics or to tumor-specific factors both at the level of the malignant cells (tumor intrinsic) or the tumor microenvironment. This review focuses on the tumor intrinsic mechanisms of drug resistance (excluding mechanism of acquired resistance due to chronic exposure). In particular, attention is given to selected mechanisms that are relevant across chemical classes of HDIs and that can aid in the design of rational combination strategies.

MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor

“…30 Although Pgp confers transporter-mediated resistance to romidepsin, this was not observed in the clinical samples studied. 14 We thus focused on nonPgp resistance mechanisms, evaluating HuT78 CTCL sublines independently selected in romidepsin in the presence of verapamil or valspodar to prevent the emergence of Pgp-mediated resistance.…”

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

“…Heterogeneity within cancer cell populations is a common survival advantage against anticancer therapy, including HDACi. In addition, previous studies have proposed different mechanisms of resistance to HDACi-mediated therapy, including differing levels of HDAC enzymes in different cells (48), HDACi efflux mechanism, and the level of P-glycoprotein (49,50), and changes in signaling pathways, including antiapoptotic factors, such as BCL-2 and NF-kB (51,52). Although the detailed mechanisms underlying differences in sensitivity were not explored, an increase in mRNA expression of class 1, 2B, and 4 HDAC enzymes ( Supplementary Fig.…”

The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression

“…For instance, the synergy of LBH589 plus doxorubicin in acute myeloid leukemia has been demonstrated (47). Furthermore, as in any new antitumor therapy, development of resistance to HDAC inhibitors can occur (48). In preclinical studies, resistance to HDAC inhibitor-induced transformed cell death has been observed in human bladder carcinoma cells (T24) and prostate cancer cells (PC3) (49)(50)(51).…”