Abstract
Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.
Highlights
Malignant melanoma arises via stepwise transformation of melanocytes and is highly aggressive when metastatic
To overcome the problem associated with culture effects on gene expression, we created cell line-derived xenografts (CDXs) by transplanting ten widely used metastatic melanoma cell lines into NOD/Shi-scid/IL2Rγnull (NOG) immunodeficient mice
These analyses revealed that Patient-derived xenografts (PDXs) and patient’s tumors (PR) exhibited similar transcriptomes but cell lines appeared different (Figure 1B)
Summary
Malignant melanoma arises via stepwise transformation of melanocytes and is highly aggressive when metastatic. Stage melanomas are often curable by resection, but prognosis and overall survival for patients with advanced-stage malignant melanoma remain poor [1, 2]. The majority of melanomas carry mitogenactivated protein kinase (MAPK) pathway-activating mutations, especially in BRAF, NRAS, NF1 [3, 4]; providing avenues for targeted therapeutic intervention. Clinical responses to targeted therapies are often initially good, most patients eventually develop acquired therapeutic resistance [5]. Disease-free survival is improved by combination regimens with small molecule inhibitors [6] and/or immunotherapy [7, 8], but most patients succumb to lethal disease. A better understanding of the molecular pathways that govern disease progression and therapeutic resistance is needed to improve clinical outcomes
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