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

Publication date: Dec 20, 2019

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.

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.

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.

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.

Ice, R.J., Chen, M., Sidorov, M., Le Ho, T., Woo, R.W.L., Rodriguez-Brotons, A., Luu, T., Jian, D., Kim, K.B., Leong, S.P., Kim, H., Kim, A., Stone, D., Nazarian, A., Oh, A., Tranah, G.J., Nosrati, M., de Semir, D., Dar, A.A., Chang, S., Desprez, P.Y., Kashani-Sabet, M., Soroceanu, L., and McAllister, S.D. Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies. 25204. 2019 Br J Cancer.

Concepts Keywords
Allele Xenograft models melanoma
BRAF Tumour
BRAF Inhibitor Concordance cancer
Cancer Medicine
Concordance Clinical medicine
Correlation Cancer
Frequency Cancer treatments
Magnitude MEK inhibitor
MEK Melanoma
Melanoma Patient derived xenograft
Mutant BRAF
Throughput Dabrafenib
Tumour Polypoid melanoma
Xenograft Drug screening

Semantics

Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
drug DRUGBANK Pralatrexate
disease MESH cancer

Original Article

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