title: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Friedman
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Amzallag
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Iulian
authors.initials: I
authors.lastname: Pruteanu-Malinici
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Subash
authors.initials: S
authors.lastname: Baniya
authors.affiliation: Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America; Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Division of Dermatopathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Leeza
authors.initials: L
authors.lastname: Hargreaves
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Vivien
authors.initials: V
authors.lastname: Igras
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America; Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America; Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D011799:Quinazolines; D013449:Sulfonamides; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D048493:Proto-Oncogene Proteins B-raf; C500926:cediranib