Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia
FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acq...
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creator | Zimmerman, Eric I. Turner, David C. Buaboonnam, Jassada Hu, Shuiying Orwick, Shelley Roberts, Michael S. Janke, Laura J. Ramachandran, Abhijit Stewart, Clinton F. Inaba, Hiroto Baker, Sharyn D. |
description | FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD−positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD−positive AML.
•The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3-activating mutations.•Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations. |
doi_str_mv | 10.1182/blood-2013-07-513044 |
format | Article |
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•The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3-activating mutations.•Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2013-07-513044</identifier><identifier>PMID: 24046014</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject><![CDATA[Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Benzimidazoles - administration & dosage ; Benzimidazoles - pharmacokinetics ; Benzimidazoles - therapeutic use ; Cell Line, Tumor ; Cell Survival - drug effects ; Drug Resistance, Neoplasm ; Drug Synergism ; Female ; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors ; fms-Like Tyrosine Kinase 3 - genetics ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - enzymology ; Leukemia, Myeloid, Acute - genetics ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Myeloid Neoplasia ; Niacinamide - administration & dosage ; Niacinamide - analogs & derivatives ; Phenylurea Compounds - administration & dosage ; Piperidines - administration & dosage ; Piperidines - pharmacokinetics ; Piperidines - therapeutic use ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - therapeutic use ; Sorafenib ; Tandem Repeat Sequences ; Xenograft Model Antitumor Assays]]></subject><ispartof>Blood, 2013-11, Vol.122 (22), p.3607-3615</ispartof><rights>2013 American Society of Hematology</rights><rights>2013 by The American Society of Hematology 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c496t-182463ed42425827c1480e6460e2650f3543d9dc2132efe8bf0323822a98b5783</citedby><cites>FETCH-LOGICAL-c496t-182463ed42425827c1480e6460e2650f3543d9dc2132efe8bf0323822a98b5783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24046014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zimmerman, Eric I.</creatorcontrib><creatorcontrib>Turner, David C.</creatorcontrib><creatorcontrib>Buaboonnam, Jassada</creatorcontrib><creatorcontrib>Hu, Shuiying</creatorcontrib><creatorcontrib>Orwick, Shelley</creatorcontrib><creatorcontrib>Roberts, Michael S.</creatorcontrib><creatorcontrib>Janke, Laura J.</creatorcontrib><creatorcontrib>Ramachandran, Abhijit</creatorcontrib><creatorcontrib>Stewart, Clinton F.</creatorcontrib><creatorcontrib>Inaba, Hiroto</creatorcontrib><creatorcontrib>Baker, Sharyn D.</creatorcontrib><title>Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia</title><title>Blood</title><addtitle>Blood</addtitle><description>FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD−positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD−positive AML.
•The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3-activating mutations.•Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations.</description><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Benzimidazoles - administration & dosage</subject><subject>Benzimidazoles - pharmacokinetics</subject><subject>Benzimidazoles - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Mutation</subject><subject>Myeloid Neoplasia</subject><subject>Niacinamide - administration & dosage</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Phenylurea Compounds - administration & dosage</subject><subject>Piperidines - administration & dosage</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - therapeutic use</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Sorafenib</subject><subject>Tandem Repeat Sequences</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1O3DAQxy1UVBboG1TIL2AYfyRxLkhoWz6klXrZno1jTxaXJF7Z2ZV4g555RJ6koUuBXjiNRqP_x_wI-crhlHMtzpouRs8EcMmgYgWXoNQemfFCaAYg4BOZAUDJVF3xA3KY8y8ArqQoPpMDoUCV0zYjt_OEQ-zsEBoaMrVuDFukdmXDkEfaR49dprGlPm1WLGEOebTDSC8XS8lult-efj-uYw47kduMSPsH7GLwtMPNPfbBHpP91nYZv7zMI_Lz8vtyfs0WP65u5hcL5lRdjmz6SJUSvRJKFFpUjisNWE4tUZQFtLJQ0tfeCS4FtqibFqSQWghb66aotDwi5zvf9abp0TscxmQ7s06ht-nBRBvM_5ch3JlV3BqpZVVAPRmonYFLMeeE7auWg3kmbv4SN8_EDVRmR3ySnbzPfRX9Q_xWbCKJ24DJZBdwcOhDQjcaH8PHCX8AkkmUFA</recordid><startdate>20131121</startdate><enddate>20131121</enddate><creator>Zimmerman, Eric I.</creator><creator>Turner, David C.</creator><creator>Buaboonnam, Jassada</creator><creator>Hu, Shuiying</creator><creator>Orwick, Shelley</creator><creator>Roberts, Michael S.</creator><creator>Janke, Laura J.</creator><creator>Ramachandran, Abhijit</creator><creator>Stewart, Clinton F.</creator><creator>Inaba, Hiroto</creator><creator>Baker, Sharyn D.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20131121</creationdate><title>Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia</title><author>Zimmerman, Eric I. ; Turner, David C. ; Buaboonnam, Jassada ; Hu, Shuiying ; Orwick, Shelley ; Roberts, Michael S. ; Janke, Laura J. ; Ramachandran, Abhijit ; Stewart, Clinton F. ; Inaba, Hiroto ; Baker, Sharyn D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c496t-182463ed42425827c1480e6460e2650f3543d9dc2132efe8bf0323822a98b5783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Benzimidazoles - administration & dosage</topic><topic>Benzimidazoles - pharmacokinetics</topic><topic>Benzimidazoles - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</topic><topic>fms-Like Tyrosine Kinase 3 - genetics</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - enzymology</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Mutation</topic><topic>Myeloid Neoplasia</topic><topic>Niacinamide - administration & dosage</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Phenylurea Compounds - administration & dosage</topic><topic>Piperidines - administration & dosage</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - therapeutic use</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Sorafenib</topic><topic>Tandem Repeat Sequences</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zimmerman, Eric I.</creatorcontrib><creatorcontrib>Turner, David C.</creatorcontrib><creatorcontrib>Buaboonnam, Jassada</creatorcontrib><creatorcontrib>Hu, Shuiying</creatorcontrib><creatorcontrib>Orwick, Shelley</creatorcontrib><creatorcontrib>Roberts, Michael S.</creatorcontrib><creatorcontrib>Janke, Laura J.</creatorcontrib><creatorcontrib>Ramachandran, Abhijit</creatorcontrib><creatorcontrib>Stewart, Clinton F.</creatorcontrib><creatorcontrib>Inaba, Hiroto</creatorcontrib><creatorcontrib>Baker, Sharyn D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zimmerman, Eric I.</au><au>Turner, David C.</au><au>Buaboonnam, Jassada</au><au>Hu, Shuiying</au><au>Orwick, Shelley</au><au>Roberts, Michael S.</au><au>Janke, Laura J.</au><au>Ramachandran, Abhijit</au><au>Stewart, Clinton F.</au><au>Inaba, Hiroto</au><au>Baker, Sharyn D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2013-11-21</date><risdate>2013</risdate><volume>122</volume><issue>22</issue><spage>3607</spage><epage>3615</epage><pages>3607-3615</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD−positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD−positive AML.
•The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3-activating mutations.•Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24046014</pmid><doi>10.1182/blood-2013-07-513044</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Benzimidazoles - administration & dosage Benzimidazoles - pharmacokinetics Benzimidazoles - therapeutic use Cell Line, Tumor Cell Survival - drug effects Drug Resistance, Neoplasm Drug Synergism Female fms-Like Tyrosine Kinase 3 - antagonists & inhibitors fms-Like Tyrosine Kinase 3 - genetics Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - enzymology Leukemia, Myeloid, Acute - genetics Male Mice Mice, Inbred NOD Mice, SCID Mutation Myeloid Neoplasia Niacinamide - administration & dosage Niacinamide - analogs & derivatives Phenylurea Compounds - administration & dosage Piperidines - administration & dosage Piperidines - pharmacokinetics Piperidines - therapeutic use Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - therapeutic use Sorafenib Tandem Repeat Sequences Xenograft Model Antitumor Assays |
title | Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia |
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