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

• Published in: PloS one Vol. 10; no. 10; p. e0140310
• Main Authors: Friedman, Adam A, Amzallag, Arnaud, Pruteanu-Malinici, Iulian, Baniya, Subash, Cooper, Zachary A, Piris, Adriano, Hargreaves, Leeza, Igras, Vivien, Frederick, Dennie T, Lawrence, Donald P, Haber, Daniel A, Flaherty, Keith T, Wargo, Jennifer A, Ramaswamy, Sridhar, Benes, Cyril H, Fisher, David E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-10-2015; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; ATP Binding Cassette Transporter, Subfamily B - metabolism; Biology; Biopsy; Biotechnology; Cancer; Cancer therapies; Cell cycle; Cell Death - drug effects; Cell Line, Tumor; Clinical trials; Dermatology; Development and progression; Dosage and administration; Drug delivery; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Drug therapy; Drugs; Gene expression; Genomics; High-Throughput Screening Assays; Hospitals; Humans; Indoles - pharmacology; Indoles - therapeutic use; Inhibitors; Kinases; Mammalian cells; MAP kinase; MDR1 protein; Medical schools; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Metastasis; Mice; Molecular Targeted Therapy; Multidrug resistance; Mutation; Oncology; P-Glycoprotein; Patient outcomes; Patients; Protein kinase; Protein transport; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - metabolism; Regression analysis; Sensitizing; Signal transduction; Skin cancer; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Tyrosine; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Xenograft Model Antitumor Assays; United States; United States > US; Texas; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140310

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.