Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma

Abstract

Therapies that target oncogenes and immune checkpoint molecules constitute a major group of treatments for metastatic melanoma. A mutation in BRAF (BRAF V600E) affects various signaling pathways, including mitogen activated protein kinase (MAPK) and PI3K/AKT/mammalian target of rapamycin (mTOR) in melanoma. Target-specific agents, such as MAPK inhibitors improve progression-free survival. However, BRAF V600E mutant melanomas treated with BRAF kinase inhibitors develop resistance. Immune checkpoint molecules, such as programmed death-1 (PD-1) and programmed death ligand-1(PD-L1), induce immune evasion of cancer cells. MAPK inhibitor resistance results from the increased expression of PD-L1. Immune checkpoint inhibitors, such as anti-PD-L1 or anti-PD-1, are main players in immune therapies designed to target metastatic melanoma. However, melanoma patients show low response rate and resistance to these inhibitors develops within 6-8 months of treatment. Epigenetic reprogramming, such as DNA methylaion and histone modification, regulates the expression of genes involved in cellular proliferation, immune checkpoints and the response to anti-cancer drugs. Histone deacetylases (HDACs) remove acetyl groups from histone and nonhistone proteins and act as transcriptional repressors. HDACs are often dysregulated in melanomas, and regulate MAPK signaling, cancer progression, and responses to various anti-cancer drugs. HDACs have been shown to regulate the expression of PD-1/PD-L1 and genes involved in immune evasion. These reports make HDACs ideal targets for the development of anti-melanoma therapeutics. We review the mechanisms of resistance to anti-melanoma therapies, including MAPK inhibitors and immune checkpoint inhibitors. We address the effects of HDAC inhibitors on the response to MAPK inhibitors and immune checkpoint inhibitors in melanoma. In addition, we discuss current progress in anti-melanoma therapies involving a combination of HDAC inhibitors, immune checkpoint inhibitors, and MAPK inhibitors.

Durable Response to Sintilimab and Chidamide in a Patient With Pegaspargase- and Immunotherapy-Resistant NK/T-Cell Lymphoma: Case Report and Literature Review

“…In addition to its direct anticancer activity, HDACi has pleiotropic immunomodulatory effects (31)(32)(33). HDACi can enhance the intratumoral infiltration of CD8+ T cells and macrophages, decrease the intratumoral infiltration of T-regulatory cells, myeloid-derived suppressor cells, and protumorigenic M2 macrophages, induce the intratumoral expression of multiple chemokines, upregulate the expression of MHC and co-stimulatory molecules, enhance immune recognition, promote tumor-specific T cell-mediated killing of cancer cells, and sensitize tumor cells to NK cell lysis (32,(34)(35)(36)(37)(38)(39)(40)(41)(42). Preclinical studies have demonstrated that HDACi can enhance the anticancer activity of immunotherapy in several types of cancers (36,37,(43)(44)(45).…”

The future of combination therapies in advanced melanoma

“…The main difficulty in designing trials specifically for this patient population is that despite the increasing amount of information on possible resistance mechanisms we do-similar to the first-line decision-still lack established markers that would allow us to point out a specific resistance mech-anism for a therapeutic decision. Therefore, drugs like HDAC inhibitors that can target several resistance mechanisms at the same time [22] might at the moment be specifically interesting in this setting.…”

Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

“…Furthermore, inhibition of specific signaling cascades in malignant cells often allows for collateral escape and continued function akin to the resistance mechanisms seen in BRAF inhibition [ 80 ], and thus, pleiotropic drugs may afford the potential for increased durability. Pro-neoplastic oncogenic driver targets involved in cell proliferation include phosphatidlyinositol-3-kinase (PI3K), bruton tyrosine kinase (BTK), MET proto-oncogene, and cyclin dependent kinases (CDKs), among many others [ 81 , 82 , 83 , 84 , 85 ]. While the plethora of oncogenic driver inhibitors act via varied mechanisms, ultimately, their targets include pathways which disrupt growth and replication (see above) or aberrant differentiation (e.g., the hedgehog pathway, cereblon, ATR3), allowing for increased drug efficacy in rapidly dividing tumor cells.…”