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Drug resistance in melanoma

Xuejiao Song, Tiantao Gao, Qian Lei, Lidan Zhang, Yuqin Yao, Jingyuan Xiong
Malignant melanoma is a devastating skin cancer due to its severe drug resistance and prompt metastasis. Piperlongumine is an anti-inflammation and tumor-suppressing natural product with defined structure. While numerous studies revealed exceptional inhibitory effects of piperlongumine on several carcinomas, few investigations were performed on melanoma. Therefore, the present study investigated the anti-tumor effects of piperlongumine on human melanoma cells in vitro, and explored the mechanisms of action...
March 15, 2018: Nutrition and Cancer
Antoneicka L Harris, Samantha E Lee, Louis K Dawson, Laura A Marlow, Brandy H Edenfield, William F Durham, Thomas J Flotte, Michael Thompson, Daniel L Small, Aidan J Synnott, Svetomir N Markovic, John A Copland
Patient-derived tumor xenograft (PDTX) mouse models were used to discover new therapies for naïve and drug resistant BRAF V600E -mutant melanoma. Tumor histology, oncogenic protein expression, and antitumor activity were comparable between patient and PDTX-matched models thereby validating PDTXs as predictive preclinical models of therapeutic response in patients. PDTX models responsive and non-responsive to BRAF/MEK standard of care (SOC) therapy were used to identify efficacious combination therapies. One such combination includes a CDK4/6 inhibitor that blocks cell cycle progression...
February 16, 2018: Oncotarget
Nina Zila, Andrea Bileck, Besnik Muqaku, Lukas Janker, Ossia M Eichhoff, Phil F Cheng, Reinhard Dummer, Mitchell P Levesque, Christopher Gerner, Verena Paulitschke
Background: MAP kinase inhibitor (MAPKi) therapy for BRAF mutated melanoma is characterized by high response rates but development of drug resistance within a median progression-free survival (PFS) of 9-12 months. Understanding mechanisms of resistance and identifying effective therapeutic alternatives is one of the most important scientific challenges in melanoma. Using proteomics, we want to specifically gain insight into the pathophysiological process of cerebral metastases. Methods: Cerebral metastases from melanoma patients were initially analyzed by a LC-MS shotgun approach performed on a QExactive HF hybrid quadrupole-orbitrap mass spectrometer...
2018: Clinical Proteomics
M Fiorentzis, H Kalirai, P Katopodis, B Seitz, A Viestenz, S E Coupland
Electrochemotherapy (ECT) enhances responsiveness to cytotoxic drugs in numerous cell lines in vitro. Clinically ECT is widely applied for skin tumor ablation and has shown efficacy in treating non-resectable colorectal liver metastases. There is limited experience of ECT for ocular tumor therapy. We investigated the cytotoxic effect of bleomycin and cisplatin in combination with electroporation on chemoresistant human uveal melanoma (UM) cell lines in vitro. Four UM cell lines (Mel 270, 92-1, OMM-1, OMM-2...
2018: Neoplasma
Jianqin Tang, Huige Zhou, Xiaoyang Hou, Liming Wang, Yaxi Li, Yanyu Pang, Chunying Chen, Guan Jiang, Yanqun Liu
Chemotherapy is an important treatment for malignant tumors; however, its efficacy and clinical application are limited by its side effects and drug resistance properties. Chemotherapy and phototherapy exhibit synergistic anti-tumor effects. In the present study, a carboxylated poly(amido-amine) (PAMAM) with low cytotoxicity was synthesized as a delivery nanocarrier for loading chemotherapeutic drugs, temozolomide (TMZ), and fluorescent dye indocyanine green (ICG). Hyaluronic acid (HA), which targets the CD44-overexpressing cancer cells, was modified on the nanocarrier surface to enhance the selective killing of melanoma cells...
March 7, 2018: Cancer Letters
Danyang Shen, Xiaoming Yu, Yan Wu, Yuanlei Chen, Gonghui Li, Feng Cheng, Liqun Xia
Retinoic acid X receptors play key roles in tumor cell proliferation, differentiation, apoptosis and angiogenesis via transcriptional regulation. Bexarotene is a specific RXRs agonist which has been granted by FDA approval for the clinical treatment of cutaneous T cell lymphoma (CTCL). Its cancer prevention and treatment potentials in various tumors have been under investigation over the past decade. Areas covered: This review summarizes the efficacy and underlying mechanisms of bexarotene for the treatment of multiple cancers based on the launched clinical trials as well as the basic studies...
March 9, 2018: Expert Review of Anticancer Therapy
Ben-Hur Neves de Oliveira, Carla Dalmaz, Fares Zeidán-Chuliá
Malignancy of cancer has been linked to distinct subsets of stem-like cells, the so-called cancer stem cells (CSCs), which persist during treatment and seem to lead to drug-resistant recurrence. Metastatic spread of cancer cells is one of the hallmarks of malignancy and contributes to most human melanoma-related deaths. Recently, overlapping groups of proteins and pathways were shown to regulate stem cell migration and cancer metastasis, raising the question of whether genes/proteins involved in stem cell pluripotency may have important implications when applied to the biology of cancer metastasis...
March 8, 2018: Medical Sciences: Open Access Journal
Jia Liu, Guoqiang Jiang, Ping Mao, Jing Zhang, Lin Zhang, Likun Liu, Jia Wang, Lawrence Owusu, Baoyin Ren, Yawei Tang, Weiling Li
Melanoma is a malignant skin cancer with considerable drug resistance. Increased expression of DNA repair genes have been reported in melanoma, and this contributes to chemotherapy resistance. GADD45A is involved in DNA repair, cell cycle arrest and apoptosis in response to physiologic or environmental stresses. In this study, we investigated the role of GADD45A in chemotherapy response. Firstly, the mRNA expression of profiled DNA repair genes in cisplatin-treated melanoma cells was detected by RT2 profilerTM PCR array...
March 7, 2018: Scientific Reports
Praveen K Bommareddy, Howard L Kaufman
Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved...
March 5, 2018: Journal of Clinical Investigation
Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer L McQuade, Roger J Liang, Mingguang Liu, Whijae Roh, Dzifa Y Duose, Fernando Cl Carapeto, Jun Li, Jessica Lf Teh, Andrew E Aplin, Merry Chen, Jianhua Zhang, Alexander J Lazar, Michael A Davies, P Andrew Futreal, Rodabe N Amaria, David Y Zhang, Jennifer A Wargo, Lawrence N Kwong
Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed...
March 1, 2018: Cancer Discovery
Abdullah Al Emran, Diego M Marzese, Dinoop Ravindran Menon, Mitchell S Stark, Joachim Torrano, Heinz Hammerlindl, Gao Zhang, Patricia Brafford, Matthew P Salomon, Nellie Nelson, Sabrina Hammerlindl, Deepesh Gupta, Gordon B Mills, Yiling Lu, Richard A Sturm, Keith Flaherty, Dave S B Hoon, Brian Gabrielli, Meenhard Herlyn, Helmut Schaider
Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi-drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays...
February 2, 2018: Oncotarget
Thomas C Beadnell, Kelsey W Nassar, Madison M Rose, Erin G Clark, Brian P Danysh, Marie-Claude Hofmann, Nikita Pozdeyev, Rebecca E Schweppe
Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway...
February 28, 2018: Oncogenesis
Raeeka Khamari, Anne Trinh, Pierre Elliott Gabert, Paola Corazao-Rozas, Samuel Riveros-Cruz, Stephane Balayssac, Myriam Malet-Martino, Salim Dekiouk, Marie Joncquel Chevalier Curt, Patrice Maboudou, Guillaume Garçon, Laura Ravasi, Pierre Guerreschi, Laurent Mortier, Bruno Quesnel, Philippe Marchetti, Jerome Kluza
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase...
February 27, 2018: Cell Death & Disease
Rochanawan Sootichote, Peti Thuwajit, Ekapot Singsuksawat, Malee Warnnissorn, Pa-Thai Yenchitsomanus, Suthinee Ithimakin, Jomjit Chantharasamee, Chanitra Thuwajit
BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer drug commonly used for the treatment of advanced breast cancer (BCA) and melanoma. Toll-like receptor 4 (TLR4) promotes the production of pro-inflammatory cytokines associated with cancer chemoresistance. This study aims to explore the effect of TLR4 in PTX resistance in triple-negative BCA and advanced melanoma and the effect of compound A (CpdA) to attenuate this resistance. METHODS: BCA and melanoma cell lines were checked for the response to PTX by cytotoxic assay...
February 27, 2018: BMC Cancer
Wei Wang, Bo Xu, Qixiang Li, Dechun Jiang, Suying Yan
The RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK (RAF/MEK/ERK) signaling cascade serves a prominent role in hepatocellular carcinoma (HCC) proliferation. Sorafenib (BAY 43‑9006) is a potent multikinase inhibitor of RAF kinases and a few receptor tyrosine kinases. Additionally, sorafenib causes apoptosis in a number of human tumor cell lines such as leukemia cell lines. Sorafenib is the first targeted drug to prolong the overall survival of patients with advanced HCC...
February 16, 2018: Molecular Medicine Reports
Renier Heijkants, Karen Willekens, Mark Schoonderwoerd, Amina Teunisse, Maaike Nieveen, Enrico Radaelli, Luuk Hawinkels, Jean-Christophe Marine, Aart Jochemsen
Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options. In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum HDAC inhibitor quisinostat and pan-CDK inhibitor flavopiridol. Both drugs are currently in clinical trials reducing time from bench to bedside...
January 19, 2018: Oncotarget
Rakshamani Tripathi, Leann S Fiore, Dana L Richards, Yuchen Yang, Jinpeng Liu, Chi Wang, Rina Plattner
The incidence of melanoma is increasing, particularly in young women, and the disease remains incurable for many because of its aggressive, metastatic nature and its high rate of resistance to conventional, targeted, and immunological agents. Cathepsins are proteases that are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave or degrade proteins that restrict cancer progression, whereas extracellular cathepsins directly cleave the extracellular matrix and activate proinvasive proteases in the tumor microenvironment...
February 20, 2018: Science Signaling
Bogos Agianian, Evripidis Gavathiotis
Oncogenic BRAF kinase deregulates the ERK signaling pathway in a large number of human tumors. FDA-approved BRAF inhibitors for BRAFV600E/K tumors have provided impressive clinical responses extending survival of melanoma patients. However, these drugs display paradoxical activation in normal tissue with BRAFWT due to RAF transactivation and priming, acquired drug resistance, and limited clinical effectiveness in non-V600 BRAF-dependent tumors, underscoring the urgent need to develop improved BRAF inhibitors...
February 20, 2018: Journal of Medicinal Chemistry
Yarong Liu, Yu Jeong Kim, Natnaree Siriwon, Jennifer A Rohrs, Zhiqiang Yu, Pin Wang
Blood vessel development is critical for the continued growth and progression of solid tumors and, therefore, makes an attractive target for improving cancer therapy. Indeed, vascular-targeted therapies have been extensively explored but they have shown minimal efficacy as monotherapies. Combretastatin A4 (CA-4) is a tubulin-binding vascular disrupting agent that selectively targets the established tumor endothelium, causing rapid vascular beak down. Despite its potent anticancer potential, the drug has dose-limiting side effects, particularly in the form of cardiovascular toxicity...
February 19, 2018: Biotechnology and Bioengineering
Xuerong Sun, Benyan Shi, Huiling Zheng, Ling Min, Jie Yang, Xiaoyi Li, Xiaoxin Liao, Weixing Huang, Mingmeng Zhang, Shun Xu, Zhe Zhu, Hongjing Cui, Xinguang Liu
Although targeted therapy and immunotherapy greatly improve the outcome of melanoma, drug resistance and low response rates still maintain the unsubstitutability of traditional chemotherapy. Cisplatin (CDDP) is widely used in different types of tumours with high response rates, but it generally has low efficiency in melanoma. The mechanisms underpinning the phenomena are not sufficiently understood. Here we demonstrated that various melanoma cell lines adopted senescence phenotype after CDDP treatment in contrast to the other types of tumour cells...
February 15, 2018: Cell Death & Disease
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