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Patient-derived xenograft platform for metastatic melanoma: a model for studying resistance to targeted therapy.

ABSTRACT: The therapeutic landscape of melanoma is rapidly changing. While targeted inhibitors yield significant responses, their clinical benefit is often limited by the early onset of drug resistance. This motivates the pursuit to establish more durable clinical responses, by developing combinatorial therapies. But while potential new combinatorial targets steadily increase in numbers, they cannot possibly all be tested in patients. Similarly, while genetically engineered mouse melanoma models have great merit, they do not capture the enormous genetic diversity and heterogeneity typical in human melanoma. Furthermore, whereas in vitro studies have many advantages, they lack the presence of micro-environmental factors, which can have a profound impact on tumor progression and therapy response. This prompted us to develop an in vivo model for human melanoma that allows for studying the dynamics of tumor progression and drug response, with concurrent evaluation and optimization of new treatment regimens. Here, we present a collection of patient-derived xenografts (PDX), derived from BRAFV600E, NRASQ61 or BRAFWT/NRASWT melanoma metastases. The BRAFV600E PDX melanomas were acquired both prior to treatment with the BRAF inhibitor vemurafenib and after resistance had occurred, including six matched pairs. We find that PDX resemble their human donors’ melanomas regarding biomarkers, chromosomal aberrations, RNA expression profiles, mutational spectrum and targeted drug resistance patterns. Mutations, previously identified to cause resistance to BRAF inhibitors, are captured in PDX derived from resistant melanomThis melanoma PDX platform represents a comprehensive public resource to study both fundamental and translational aspects of melanoma progression and treatment in a physiologically relevant setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66539 | GEO | 2016/05/27

SECONDARY ACCESSION(S): PRJNA277227

REPOSITORIES: GEO

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Project description:Fifty percent of cutaneous melanomas are driven by activated BRAFV600E, but tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to MAPK pathway inhibition we identified the combination PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ERBB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720. To identify potential mechanisms of resistance to PLX4720 treatment and synergy with lapatinib treatment we performed a multi-platform functional genomics analysis to profile the genome as well as the transcriptional and proteomic responses of these cell lines to treatment with PLX4720. We found modest levels of resistance correlated with the zygosity of the BRAF V600E allele and RTK mutational status. Layered over base-line resistance was substantial upregulation of many ERBB pathway genes in response to BRaf inhibition, thus generating the vulnerability to combination with lapatinib. The transcriptional responses of ERBB pathway genes are associated with a number of transcription factors, including ETS2 and its associated cofactors that represent a convergent regulatory mechanism conferring synergistic drug susceptibility in the context of diverse mutational landscapes. 12 BRAF mutant melanomas and 4 melanomas with WT BRAF were exposed plx4720 treatment to evaluate their responses after 8 hours of treatment. 5 of the 12 BRAF mutant melanomas responses were also evaluated in response to the treatment of lapatinib alone, masitinib alone, the combination of lapatinib with plx4720, or the combination of masitinib with plx4720. All samples were run in at least triplicate.

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Patient-derived xenograft platform for metastatic melanoma: a model for studying resistance to targeted therapy.

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