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

Ryan J Ice,Hankyul Kim,Pierre-Yves Desprez,Angela Kim,Michelle Chen,Des Stone,Kevin B Kim,Ari Nazarian,Tri Luu,Mohammed Kashani‐Sabet ,Stanley P L Leong ,Alyssia Oh,David De Semir,Liliana Soroceanu,Tam Le Ho,Altaf A Dar,Stephen H Chang ,Damon Jian,Maxim Sidorov ,Mehdi Nosrati,Rinette W.l Woo ,Aida Rodriguez-Brotons,Gregory J Tranah,Sean D Mcallister

doi:10.1038/s41416-019-0696-y

Abstract

BackgroundPatient-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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.

Highlights

Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients
Melanoma PDX cultures (PDXC) were screened in an high-throughput drug-screening (HTDS) format (Supplementary Methods) against a 6point concentration–response curve of drugs chosen primarily based on the following criteria: (1) The drug is FDA-approved or in clinical trials; (2) The drug is available for research purposes; (3) Pharmacokinetic (PK) data in humans are available
It is important to determine whether the response to specific targeted therapies in derivatives of PDXs, such as PDXCs, show a direct correlation to the response observed in vivo

Summary

Introduction

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 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. 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. Additional treatment strategies are needed for patients with cancers resistant to the standard-of-care.[3] In the development of effective personalised therapy platforms for cancer patients, research has focused on the use of patient-derived xenografts (PDXs). Their analysis showed that the response in PDXs predicted the response in the patient

Objectives

Methods

Results

Conclusion