Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment

Adam A Friedman,Dennie T Frederick,Sridhar Ramaswamy,Keith T Flaherty,Daniel A Haber,Vivien Igras,Adriano Piris,Subash Baniya,Donald P Lawrence,Zachary A Cooper,Leeza Hargreaves,David E Fisher,Arnaud Amzallag,Jennifer A Wargo,Iulian Pruteanu-Malinici,Cyril H Benes,Suzie Chen

doi:10.1371/journal.pone.0140310

Abstract

A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

Highlights

Response rates within genetically-selected subpopulations of solid tumor cancer patients can be high, such as 60–80% among BRAFV600E mutant melanoma patients receiving the BRAF inhibitor vemurafenib [1], few patients achieve single-agent complete responses
Since we were interested in finding drug combinations with potential for clinical translation and for which mechanism of action would be tractable, we selected well-characterized oncology drugs approved by the Food and Drug Administration (FDA) or in late clinical trials; two-thirds of these agents have been in clinical use (Fig 1A and S1 Table)
Given the strong synergy between vincristine and lapatinib in A375 but not WM451Lu cells, we investigated whether differential multidrug resistance (MDR) family expression may underlie the cell line specificity of the synergistic interaction

Summary

Introduction

Response rates within genetically-selected subpopulations of solid tumor cancer patients can be high, such as 60–80% among BRAFV600E mutant melanoma patients receiving the BRAF inhibitor vemurafenib [1], few patients achieve single-agent complete responses. Candidate-based discovery of combination drug targets such as sequencing tumors for additional driver somatic mutations [8] or unbiased RNAi or cDNA screens can yield actionable targets These approaches may miss potential high-order interactions with inhibitors targeting multiple proteins and their clinical relevance may depend upon lengthy drug discovery efforts around novel targets. Based on strong context dependency seen for single agent activity it is expected that combinations’ activity and synergism will be context specific It is not yet clear whether combinations of targeted agents could be efficacious across a broad range of tumor subtype, making them applicable to more patients than their single agent constituent or whether resistance needs to be addressed by a large number of context specific combinations addressing smaller groups of patients than the constituting single agents. Melanoma was selected in light of the availability of a large number of cell lines harboring a common mutated oncogene (BRAFV600E) and a validated targeted therapy

Methods

Results

Conclusion