Abstract
Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366-77. ©2016 AACR.
Highlights
Metastatic melanoma is a highly aggressive disease characterized by high mortality and poor chemotherapeutic response
B, FAK phosphorylation (Tyr576/Tyr577; phosphorylated FAK (pFAK)), pro-PDGFD, and b-actin levels were detected by Western blot analysis in A375 cells transfected with siNeg or siZIC5
In a vemurafenib-resistant cell line, ZIC5 or PDGFD knockdown combined with PLX4032 treatment significantly reduced phosphorylated ERK levels, while PLX4032 treatment alone did not (Fig. 7J). These results demonstrate that ZIC5-mediated signaling contributes to ERK activation in vemurafenib-resistant melanoma (Fig. 7K), and that targeting of ZIC5 and PDGFD may provide an effective therapy for BRAF inhibitor–resistant melanoma
Summary
Metastatic melanoma is a highly aggressive disease characterized by high mortality and poor chemotherapeutic response. Despite the recent conception of novel therapeutic approaches, such as molecular targeted therapies and immunotherapies [1], the prognosis remains very poor. 50% melanomas harbor an activating mutation in the BRAF gene, leading to aberrant MEK–ERK signaling pathway activation that promotes cell growth and survival. BRAF kinase inhibitors such as vemurafenib have improved the rates of overall and progression-free survival in melanoma patients with BRAF mutations [2]. Tumor recurrence frequently occurs as a result of acquired resistance to BRAF inhibitors; the identification of novel drug targets based on molecular mechanisms of malignant melanoma is urgently required. The epithelial–mesenchymal transition (EMT) is a process whereby cancer cells acquire mesenchymal phenotypes and subsequently lose their epithelial characteristics, resulting in enhanced malignancy, cancer stem cell-like properties, and therapeutic resistance. A previous microarray analysis demonstrated that the EMT transcriptional program is involved in
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