Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
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...
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| Veröffentlicht in: | PloS one 2015-10, Vol.10 (10), p.e0140310 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0140310 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0140310</identifier><identifier>PMID: 26461489</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PloS one, 2015-10, Vol.10 (10), p.e0140310</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Friedman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Friedman et al 2015 Friedman et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c719t-84b0e39da4612d613b22d9f18d60d13f284b5f8acd29ebb7bfa88f73fa5cf2a63</citedby><cites>FETCH-LOGICAL-c719t-84b0e39da4612d613b22d9f18d60d13f284b5f8acd29ebb7bfa88f73fa5cf2a63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604168/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604168/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26461489$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Friedman, Adam A</creatorcontrib><creatorcontrib>Amzallag, Arnaud</creatorcontrib><creatorcontrib>Pruteanu-Malinici, Iulian</creatorcontrib><creatorcontrib>Baniya, Subash</creatorcontrib><creatorcontrib>Cooper, Zachary A</creatorcontrib><creatorcontrib>Piris, Adriano</creatorcontrib><creatorcontrib>Hargreaves, Leeza</creatorcontrib><creatorcontrib>Igras, Vivien</creatorcontrib><creatorcontrib>Frederick, Dennie T</creatorcontrib><creatorcontrib>Lawrence, Donald P</creatorcontrib><creatorcontrib>Haber, Daniel A</creatorcontrib><creatorcontrib>Flaherty, Keith T</creatorcontrib><creatorcontrib>Wargo, Jennifer A</creatorcontrib><creatorcontrib>Ramaswamy, Sridhar</creatorcontrib><creatorcontrib>Benes, Cyril H</creatorcontrib><creatorcontrib>Fisher, David E</creatorcontrib><title>Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis</subject><subject>ATP Binding Cassette Transporter, Subfamily B - metabolism</subject><subject>Biology</subject><subject>Biopsy</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Death - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Clinical trials</subject><subject>Dermatology</subject><subject>Development and progression</subject><subject>Dosage and administration</subject><subject>Drug delivery</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Gene expression</subject><subject>Genomics</subject><subject>High-Throughput Screening Assays</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Mammalian cells</subject><subject>MAP kinase</subject><subject>MDR1 protein</subject><subject>Medical schools</subject><subject>Melanoma</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - pathology</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Molecular Targeted Therapy</subject><subject>Multidrug resistance</subject><subject>Mutation</subject><subject>Oncology</subject><subject>P-Glycoprotein</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Protein kinase</subject><subject>Protein transport</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Quinazolines - therapeutic use</subject><subject>Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors</subject><subject>Receptors, Platelet-Derived Growth Factor - metabolism</subject><subject>Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors</subject><subject>Receptors, Vascular Endothelial Growth Factor - metabolism</subject><subject>Regression analysis</subject><subject>Sensitizing</subject><subject>Signal transduction</subject><subject>Skin cancer</subject><subject>Sulfonamides - pharmacology</subject><subject>Sulfonamides - therapeutic use</subject><subject>Tyrosine</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular endothelial growth factor receptors</subject><subject>Xenograft Model Antitumor 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Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Friedman, Adam A</au><au>Amzallag, Arnaud</au><au>Pruteanu-Malinici, Iulian</au><au>Baniya, Subash</au><au>Cooper, Zachary A</au><au>Piris, Adriano</au><au>Hargreaves, Leeza</au><au>Igras, Vivien</au><au>Frederick, Dennie T</au><au>Lawrence, Donald P</au><au>Haber, Daniel A</au><au>Flaherty, Keith T</au><au>Wargo, Jennifer A</au><au>Ramaswamy, Sridhar</au><au>Benes, Cyril H</au><au>Fisher, David E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-10-13</date><risdate>2015</risdate><volume>10</volume><issue>10</issue><spage>e0140310</spage><pages>e0140310-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26461489</pmid><doi>10.1371/journal.pone.0140310</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-10, Vol.10 (10), p.e0140310 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1721911104 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; 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 |
| title | Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment |
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