Polypharmacology-based ceritinib repurposing using integrated functional proteomics
A systems chemical biology approach to characterize beneficial off-target effects revealed a polypharmacology mechanism for the multikinase inhibitor ceritinib and a repurposing opportunity through rational design of a synergistic drug combination. Targeted drugs are effective when they directly inh...
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| Veröffentlicht in: | Nature chemical biology 2017-12, Vol.13 (12), p.1222-1231 |
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| creator | Kuenzi, Brent M Remsing Rix, Lily L Stewart, Paul A Fang, Bin Kinose, Fumi Bryant, Annamarie T Boyle, Theresa A Koomen, John M Haura, Eric B Rix, Uwe |
| description | A systems chemical biology approach to characterize beneficial off-target effects revealed a polypharmacology mechanism for the multikinase inhibitor ceritinib and a repurposing opportunity through rational design of a synergistic drug combination.
Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several
ALK
-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the noncanonical targets IGF1R, FAK1, RSK1 and RSK2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, combination of ceritinib with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multikinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates. |
| doi_str_mv | 10.1038/nchembio.2489 |
| format | Article |
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Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several
ALK
-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the noncanonical targets IGF1R, FAK1, RSK1 and RSK2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, combination of ceritinib with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multikinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates.</description><identifier>ISSN: 1552-4450</identifier><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/nchembio.2489</identifier><identifier>PMID: 28991240</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/67/1059 ; 631/92/275 ; 631/92/360 ; 631/92/475 ; 82/51 ; 82/58 ; 96/95 ; 96/98 ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biochemical Engineering ; Biochemistry ; Biomarkers ; Bioorganic Chemistry ; Cancer ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Biology ; Cell Line, Tumor ; Cell Survival - drug effects ; Chemistry ; Chemistry/Food Science ; Dose-Response Relationship, Drug ; Drug development ; Drug Screening Assays, Antitumor ; Enzyme inhibitors ; Humans ; Inhibitors ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Lymphoma ; Microtubules - drug effects ; Molecular Structure ; Paclitaxel ; Pharmacology ; Polypharmacology ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein-tyrosine kinase ; Proteomics ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - metabolism ; Ribonucleic acid ; Ribosomal protein S6 kinase ; RNA ; RNA Interference ; RNA-mediated interference ; Signaling ; Structure-Activity Relationship ; Sulfones - chemistry ; Sulfones - pharmacology ; Target recognition ; Taxol ; Tumor cell lines</subject><ispartof>Nature chemical biology, 2017-12, Vol.13 (12), p.1222-1231</ispartof><rights>Springer Nature America, Inc. 2017</rights><rights>Copyright Nature Publishing Group Dec 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-81fa8a67c54fc43f5cac7bda38a3f3b897da310d184dbbf743a42b58772044523</citedby><cites>FETCH-LOGICAL-c454t-81fa8a67c54fc43f5cac7bda38a3f3b897da310d184dbbf743a42b58772044523</cites><orcidid>0000-0002-8242-2770</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nchembio.2489$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nchembio.2489$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28991240$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuenzi, Brent M</creatorcontrib><creatorcontrib>Remsing Rix, Lily L</creatorcontrib><creatorcontrib>Stewart, Paul A</creatorcontrib><creatorcontrib>Fang, Bin</creatorcontrib><creatorcontrib>Kinose, Fumi</creatorcontrib><creatorcontrib>Bryant, Annamarie T</creatorcontrib><creatorcontrib>Boyle, Theresa A</creatorcontrib><creatorcontrib>Koomen, John M</creatorcontrib><creatorcontrib>Haura, Eric B</creatorcontrib><creatorcontrib>Rix, Uwe</creatorcontrib><title>Polypharmacology-based ceritinib repurposing using integrated functional proteomics</title><title>Nature chemical biology</title><addtitle>Nat Chem Biol</addtitle><addtitle>Nat Chem Biol</addtitle><description>A systems chemical biology approach to characterize beneficial off-target effects revealed a polypharmacology mechanism for the multikinase inhibitor ceritinib and a repurposing opportunity through rational design of a synergistic drug combination.
Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several
ALK
-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the noncanonical targets IGF1R, FAK1, RSK1 and RSK2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, combination of ceritinib with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multikinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates.</description><subject>631/67/1059</subject><subject>631/92/275</subject><subject>631/92/360</subject><subject>631/92/475</subject><subject>82/51</subject><subject>82/58</subject><subject>96/95</subject><subject>96/98</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Biomarkers</subject><subject>Bioorganic Chemistry</subject><subject>Cancer</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chemistry</subject><subject>Chemistry/Food Science</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug development</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme inhibitors</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Lymphoma</subject><subject>Microtubules - drug effects</subject><subject>Molecular Structure</subject><subject>Paclitaxel</subject><subject>Pharmacology</subject><subject>Polypharmacology</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-tyrosine kinase</subject><subject>Proteomics</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptor Protein-Tyrosine Kinases - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuenzi, Brent M</au><au>Remsing Rix, Lily L</au><au>Stewart, Paul A</au><au>Fang, Bin</au><au>Kinose, Fumi</au><au>Bryant, Annamarie T</au><au>Boyle, Theresa A</au><au>Koomen, John M</au><au>Haura, Eric B</au><au>Rix, Uwe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Polypharmacology-based ceritinib repurposing using integrated functional proteomics</atitle><jtitle>Nature chemical biology</jtitle><stitle>Nat Chem Biol</stitle><addtitle>Nat Chem Biol</addtitle><date>2017-12-01</date><risdate>2017</risdate><volume>13</volume><issue>12</issue><spage>1222</spage><epage>1231</epage><pages>1222-1231</pages><issn>1552-4450</issn><eissn>1552-4469</eissn><abstract>A systems chemical biology approach to characterize beneficial off-target effects revealed a polypharmacology mechanism for the multikinase inhibitor ceritinib and a repurposing opportunity through rational design of a synergistic drug combination.
Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several
ALK
-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the noncanonical targets IGF1R, FAK1, RSK1 and RSK2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, combination of ceritinib with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multikinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>28991240</pmid><doi>10.1038/nchembio.2489</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-8242-2770</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1059 631/92/275 631/92/360 631/92/475 82/51 82/58 96/95 96/98 Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biochemical Engineering Biochemistry Biomarkers Bioorganic Chemistry Cancer Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Biology Cell Line, Tumor Cell Survival - drug effects Chemistry Chemistry/Food Science Dose-Response Relationship, Drug Drug development Drug Screening Assays, Antitumor Enzyme inhibitors Humans Inhibitors Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Lymphoma Microtubules - drug effects Molecular Structure Paclitaxel Pharmacology Polypharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-tyrosine kinase Proteomics Pyrimidines - chemistry Pyrimidines - pharmacology Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - metabolism Ribonucleic acid Ribosomal protein S6 kinase RNA RNA Interference RNA-mediated interference Signaling Structure-Activity Relationship Sulfones - chemistry Sulfones - pharmacology Target recognition Taxol Tumor cell lines |
| title | Polypharmacology-based ceritinib repurposing using integrated functional proteomics |
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