Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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, BRAFV600E 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 non-histone 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.
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PMID:Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma. 3262 12

Despite groundbreaking new treatments such as checkpoint inhibition and targeted therapy, the overall response and survival rates are limited in patients with metastatic melanoma. Here, we hypothesize that melatonin and its metabolites could be promising boosters of the efficacy of BRAF/MEK inhibitors in patients with advanced melanoma. Melatonin, a well-known endogenous synchronizer of the circadian biorhythm has a variety of promising effects for melanoma biology. It regulates proliferation, apoptosis and oxidative phosphorylation via melatonin receptors, and receptor-independent pathways due to its lipophilicity. By means of interfering with the above cellular pathways, melatonin and related compounds may alter the cAMP-PKA-MITF axis, modulate tumor cell metabolism, affect MAPK signalling pathway thereby enhancing the suppressive effect of BRAF/MEK inhibitors on melanoma cell growth, and survival. Such findings could fuel preclinical studies and clinical studies where melatonin or its metabolites are combined with targeted therapy to better treat patients with metastatic melanoma.
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PMID:Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma? 3263 50

Targeted BRAF(V600E) suppression by selective BRAF inhibitors (BRAFi's, e.g. vemurafenib and dabrafenib) has led to a sea change in the treatment of metastatic melanoma (Long et al. 2014). Despite frequent upfront responses, acquired resistance has compromised long-term applicability (Sosman et al. 2012). Among the various mechanisms of resistance, activation of multiple receptor tyrosine kinases (RTKs) is a known critical factor that contributes to vemurafenib resistance (Luebker and Koepsell 2019), EGFR activation has been recurrently identified in a set of vemurafenib-resistant melanomas (Corcoran et al. 2012; Ji et al. 2015; Webster et al. 2014), but little is known about how EGFR, or possibly other RTKs, becomes activated. Here we report that ACK1, a protein kinase that modulates EGFR turnover, is downregulated in vemurafenib-resistant melanoma cells. We also found that ACK1 depletion with shRNA decreased EGFR degradation when activated by EGF, increased EGFR protein expression, and conferred resistance to BRAFi's both in vitro and in vivo. Vemurafenib resistance mediated by ACK1 inhibition can be reversed by EGFR inhibitor gefitinib. Our data indicate that ACK1 loss may be a post-transcriptional mechanism that increases EGFR signaling and contributes to drug resistance.
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PMID:Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF inhibition. 3315 68


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