Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies

Abstract

Background Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. Methods We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. Results The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. Conclusions The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.

Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9

“…Cells generated from the PDX model (referred to as PDXC), were grown in culture as spheroids under tumor stem cell conditions, without fetal bovine serum, to better conserve the phenotype and genotype of the original tumor, and to mimic a 3D tumor tissue environment 17 . We performed a high-throughput drug screen (HTDS) 18 using the PDXC designated as CHNG6, and identified a high level of sensitivity to the CDK2/5/9 inhibitor, dinaciclib (Fig. 1 A).…”

3D-Printed Collagen Scaffolds Promote Maintenance of Cryopreserved Patients-Derived Melanoma Explants

“…To investigate the screening of candidate drugs for potential antimelanoma action, an MPDX model can be used for the propagation and expansion of patient tumors by implanting tumor fragments or single cells into immunodeficient NSG TM mice [ 6 , 7 , 8 ]. However, minimal research utilizes MPDX models due to their considerable expense and prolonged time frame (often over 2 months) required for initial set-up.…”

“…Advanced melanoma is extremely challenging to prevent, detect, and monitor, as well as being resistant to therapy [ 5 ]. To explore how melanoma evades targeted therapies, patient-derived melanoma xenograft (PDX) was developed through transplanting surgical patient-derived tumor specimens or well-validated cancer cell lines into immunocompromised mice [ 6 , 7 , 8 , 9 ]. In general, traditional two-dimensional (2D) patient-derived primary melanoma cells and melanoma cell lines do not necessarily reflect the molecular and biological properties of the original melanoma in patients [ 1 ].…”

“…In general, traditional two-dimensional (2D) patient-derived primary melanoma cells and melanoma cell lines do not necessarily reflect the molecular and biological properties of the original melanoma in patients [ 1 ]. The PDX model is known as a patient “avatar” [ 6 , 7 , 8 , 9 ]. PDX models have been demonstrated to more closely resemble the original tumor due to the level of heterogeneity and the properties of the microenvironment, retaining the cellular complexity, cytogenetics, and stromal architecture maintained in the in vivo system [ 6 , 7 , 8 , 9 ].…”

“…The PDX model is known as a patient “avatar” [ 6 , 7 , 8 , 9 ]. PDX models have been demonstrated to more closely resemble the original tumor due to the level of heterogeneity and the properties of the microenvironment, retaining the cellular complexity, cytogenetics, and stromal architecture maintained in the in vivo system [ 6 , 7 , 8 , 9 ]. However, a limitation of PDX models is the possibility of original human stromal cells in tumors dissected from patients being gradually replaced by murine stromal cells as the xenograft grows.…”