Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer
Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To...
Gespeichert in:
| Veröffentlicht in: | Nature cancer 2022-02, Vol.3 (2), p.219-231 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 231 |
|---|---|
| container_issue | 2 |
| container_start_page | 219 |
| container_title | Nature cancer |
| container_volume | 3 |
| creator | Gavert, Nancy Zwang, Yaara Weiser, Roi Greenberg, Orli Halperin, Sharon Jacobi, Oded Mallel, Giuseppe Sandler, Oded Berger, Adi Jacob Stossel, Erez Rotin, Daniil Grinshpun, Albert Kamer, Iris Bar, Jair Pines, Guy Saidian, Daniel Bar, Ilan Golan, Shay Rosenbaum, Eli Nadu, Andrei Ben-Ami, Eytan Weitzen, Rony Nechushtan, Hovav Golan, Talia Brenner, Baruch Nissan, Aviram Margalit, Ofer Hershkovitz, Dov Lahat, Guy Straussman, Ravid |
| description | Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRAS
mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC. |
| doi_str_mv | 10.1038/s43018-021-00325-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2628295164</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2628295164</sourcerecordid><originalsourceid>FETCH-LOGICAL-c303t-9c2c95fbf05c285a64963170aad255a1ba5710381f48f15f7d0932802e96abfb3</originalsourceid><addsrcrecordid>eNpNkctOBCEQRYnRqBnnB1wYlm5aoWj6sTRmfESNC3VNaBoU0wMt0MbxZ_xV0VHjqqrg3lNJXYT2KTmihDXHsWSENgUBWhDCgBewgXahqqCgrKw3__U7aB7jMyEEOKW8bbbRDuO05AzqXfSxeMOv9tVjHx6l82k1WoXVNKQp6IiNDziunA6PNqb8kZ50kOMKj8H6YJN9l8l6h22vXbImv-c5t0UctbImGzJk9C5mVPJY-WVnne7xzeIKS9fju6CwdU-2s2uMy5LBB62SHLCSTumwh7aMHKKe_9QZejhb3J9eFNe355enJ9eFYoSlolWgWm46Q7iChsuqbCtGayJlD5xL2klef52NmrIxlJu6Jy2DhoBuK9mZjs3Q4Zo7Bv8y6ZjE0kalh0E67acooIIGWk6rMkthLVXBxxi0EfkcSxlWghLxtUSssxE5G_GdjYBsOvjhT91S93-W3yTYJ80vjaQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2628295164</pqid></control><display><type>article</type><title>Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Gavert, Nancy ; Zwang, Yaara ; Weiser, Roi ; Greenberg, Orli ; Halperin, Sharon ; Jacobi, Oded ; Mallel, Giuseppe ; Sandler, Oded ; Berger, Adi Jacob ; Stossel, Erez ; Rotin, Daniil ; Grinshpun, Albert ; Kamer, Iris ; Bar, Jair ; Pines, Guy ; Saidian, Daniel ; Bar, Ilan ; Golan, Shay ; Rosenbaum, Eli ; Nadu, Andrei ; Ben-Ami, Eytan ; Weitzen, Rony ; Nechushtan, Hovav ; Golan, Talia ; Brenner, Baruch ; Nissan, Aviram ; Margalit, Ofer ; Hershkovitz, Dov ; Lahat, Guy ; Straussman, Ravid</creator><creatorcontrib>Gavert, Nancy ; Zwang, Yaara ; Weiser, Roi ; Greenberg, Orli ; Halperin, Sharon ; Jacobi, Oded ; Mallel, Giuseppe ; Sandler, Oded ; Berger, Adi Jacob ; Stossel, Erez ; Rotin, Daniil ; Grinshpun, Albert ; Kamer, Iris ; Bar, Jair ; Pines, Guy ; Saidian, Daniel ; Bar, Ilan ; Golan, Shay ; Rosenbaum, Eli ; Nadu, Andrei ; Ben-Ami, Eytan ; Weitzen, Rony ; Nechushtan, Hovav ; Golan, Talia ; Brenner, Baruch ; Nissan, Aviram ; Margalit, Ofer ; Hershkovitz, Dov ; Lahat, Guy ; Straussman, Ravid</creatorcontrib><description>Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRAS
mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.</description><identifier>ISSN: 2662-1347</identifier><identifier>EISSN: 2662-1347</identifier><identifier>DOI: 10.1038/s43018-021-00325-2</identifier><identifier>PMID: 35145327</identifier><language>eng</language><publisher>England</publisher><subject>Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms - drug therapy ; Humans ; Mitogen-Activated Protein Kinase Kinases ; Mutation ; Tumor Microenvironment</subject><ispartof>Nature cancer, 2022-02, Vol.3 (2), p.219-231</ispartof><rights>2021. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c303t-9c2c95fbf05c285a64963170aad255a1ba5710381f48f15f7d0932802e96abfb3</citedby><cites>FETCH-LOGICAL-c303t-9c2c95fbf05c285a64963170aad255a1ba5710381f48f15f7d0932802e96abfb3</cites><orcidid>0000-0002-9205-5820 ; 0000-0002-9476-329X ; 0000-0002-3351-5719 ; 0000-0003-1639-4684</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35145327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gavert, Nancy</creatorcontrib><creatorcontrib>Zwang, Yaara</creatorcontrib><creatorcontrib>Weiser, Roi</creatorcontrib><creatorcontrib>Greenberg, Orli</creatorcontrib><creatorcontrib>Halperin, Sharon</creatorcontrib><creatorcontrib>Jacobi, Oded</creatorcontrib><creatorcontrib>Mallel, Giuseppe</creatorcontrib><creatorcontrib>Sandler, Oded</creatorcontrib><creatorcontrib>Berger, Adi Jacob</creatorcontrib><creatorcontrib>Stossel, Erez</creatorcontrib><creatorcontrib>Rotin, Daniil</creatorcontrib><creatorcontrib>Grinshpun, Albert</creatorcontrib><creatorcontrib>Kamer, Iris</creatorcontrib><creatorcontrib>Bar, Jair</creatorcontrib><creatorcontrib>Pines, Guy</creatorcontrib><creatorcontrib>Saidian, Daniel</creatorcontrib><creatorcontrib>Bar, Ilan</creatorcontrib><creatorcontrib>Golan, Shay</creatorcontrib><creatorcontrib>Rosenbaum, Eli</creatorcontrib><creatorcontrib>Nadu, Andrei</creatorcontrib><creatorcontrib>Ben-Ami, Eytan</creatorcontrib><creatorcontrib>Weitzen, Rony</creatorcontrib><creatorcontrib>Nechushtan, Hovav</creatorcontrib><creatorcontrib>Golan, Talia</creatorcontrib><creatorcontrib>Brenner, Baruch</creatorcontrib><creatorcontrib>Nissan, Aviram</creatorcontrib><creatorcontrib>Margalit, Ofer</creatorcontrib><creatorcontrib>Hershkovitz, Dov</creatorcontrib><creatorcontrib>Lahat, Guy</creatorcontrib><creatorcontrib>Straussman, Ravid</creatorcontrib><title>Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer</title><title>Nature cancer</title><addtitle>Nat Cancer</addtitle><description>Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRAS
mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.</description><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Humans</subject><subject>Mitogen-Activated Protein Kinase Kinases</subject><subject>Mutation</subject><subject>Tumor Microenvironment</subject><issn>2662-1347</issn><issn>2662-1347</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkctOBCEQRYnRqBnnB1wYlm5aoWj6sTRmfESNC3VNaBoU0wMt0MbxZ_xV0VHjqqrg3lNJXYT2KTmihDXHsWSENgUBWhDCgBewgXahqqCgrKw3__U7aB7jMyEEOKW8bbbRDuO05AzqXfSxeMOv9tVjHx6l82k1WoXVNKQp6IiNDziunA6PNqb8kZ50kOMKj8H6YJN9l8l6h22vXbImv-c5t0UctbImGzJk9C5mVPJY-WVnne7xzeIKS9fju6CwdU-2s2uMy5LBB62SHLCSTumwh7aMHKKe_9QZejhb3J9eFNe355enJ9eFYoSlolWgWm46Q7iChsuqbCtGayJlD5xL2klef52NmrIxlJu6Jy2DhoBuK9mZjs3Q4Zo7Bv8y6ZjE0kalh0E67acooIIGWk6rMkthLVXBxxi0EfkcSxlWghLxtUSssxE5G_GdjYBsOvjhT91S93-W3yTYJ80vjaQ</recordid><startdate>20220201</startdate><enddate>20220201</enddate><creator>Gavert, Nancy</creator><creator>Zwang, Yaara</creator><creator>Weiser, Roi</creator><creator>Greenberg, Orli</creator><creator>Halperin, Sharon</creator><creator>Jacobi, Oded</creator><creator>Mallel, Giuseppe</creator><creator>Sandler, Oded</creator><creator>Berger, Adi Jacob</creator><creator>Stossel, Erez</creator><creator>Rotin, Daniil</creator><creator>Grinshpun, Albert</creator><creator>Kamer, Iris</creator><creator>Bar, Jair</creator><creator>Pines, Guy</creator><creator>Saidian, Daniel</creator><creator>Bar, Ilan</creator><creator>Golan, Shay</creator><creator>Rosenbaum, Eli</creator><creator>Nadu, Andrei</creator><creator>Ben-Ami, Eytan</creator><creator>Weitzen, Rony</creator><creator>Nechushtan, Hovav</creator><creator>Golan, Talia</creator><creator>Brenner, Baruch</creator><creator>Nissan, Aviram</creator><creator>Margalit, Ofer</creator><creator>Hershkovitz, Dov</creator><creator>Lahat, Guy</creator><creator>Straussman, Ravid</creator><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>7X8</scope><orcidid>https://orcid.org/0000-0002-9205-5820</orcidid><orcidid>https://orcid.org/0000-0002-9476-329X</orcidid><orcidid>https://orcid.org/0000-0002-3351-5719</orcidid><orcidid>https://orcid.org/0000-0003-1639-4684</orcidid></search><sort><creationdate>20220201</creationdate><title>Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer</title><author>Gavert, Nancy ; Zwang, Yaara ; Weiser, Roi ; Greenberg, Orli ; Halperin, Sharon ; Jacobi, Oded ; Mallel, Giuseppe ; Sandler, Oded ; Berger, Adi Jacob ; Stossel, Erez ; Rotin, Daniil ; Grinshpun, Albert ; Kamer, Iris ; Bar, Jair ; Pines, Guy ; Saidian, Daniel ; Bar, Ilan ; Golan, Shay ; Rosenbaum, Eli ; Nadu, Andrei ; Ben-Ami, Eytan ; Weitzen, Rony ; Nechushtan, Hovav ; Golan, Talia ; Brenner, Baruch ; Nissan, Aviram ; Margalit, Ofer ; Hershkovitz, Dov ; Lahat, Guy ; Straussman, Ravid</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c303t-9c2c95fbf05c285a64963170aad255a1ba5710381f48f15f7d0932802e96abfb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Humans</topic><topic>Mitogen-Activated Protein Kinase Kinases</topic><topic>Mutation</topic><topic>Tumor Microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gavert, Nancy</creatorcontrib><creatorcontrib>Zwang, Yaara</creatorcontrib><creatorcontrib>Weiser, Roi</creatorcontrib><creatorcontrib>Greenberg, Orli</creatorcontrib><creatorcontrib>Halperin, Sharon</creatorcontrib><creatorcontrib>Jacobi, Oded</creatorcontrib><creatorcontrib>Mallel, Giuseppe</creatorcontrib><creatorcontrib>Sandler, Oded</creatorcontrib><creatorcontrib>Berger, Adi Jacob</creatorcontrib><creatorcontrib>Stossel, Erez</creatorcontrib><creatorcontrib>Rotin, Daniil</creatorcontrib><creatorcontrib>Grinshpun, Albert</creatorcontrib><creatorcontrib>Kamer, Iris</creatorcontrib><creatorcontrib>Bar, Jair</creatorcontrib><creatorcontrib>Pines, Guy</creatorcontrib><creatorcontrib>Saidian, Daniel</creatorcontrib><creatorcontrib>Bar, Ilan</creatorcontrib><creatorcontrib>Golan, Shay</creatorcontrib><creatorcontrib>Rosenbaum, Eli</creatorcontrib><creatorcontrib>Nadu, Andrei</creatorcontrib><creatorcontrib>Ben-Ami, Eytan</creatorcontrib><creatorcontrib>Weitzen, Rony</creatorcontrib><creatorcontrib>Nechushtan, Hovav</creatorcontrib><creatorcontrib>Golan, Talia</creatorcontrib><creatorcontrib>Brenner, Baruch</creatorcontrib><creatorcontrib>Nissan, Aviram</creatorcontrib><creatorcontrib>Margalit, Ofer</creatorcontrib><creatorcontrib>Hershkovitz, Dov</creatorcontrib><creatorcontrib>Lahat, Guy</creatorcontrib><creatorcontrib>Straussman, Ravid</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Nature cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gavert, Nancy</au><au>Zwang, Yaara</au><au>Weiser, Roi</au><au>Greenberg, Orli</au><au>Halperin, Sharon</au><au>Jacobi, Oded</au><au>Mallel, Giuseppe</au><au>Sandler, Oded</au><au>Berger, Adi Jacob</au><au>Stossel, Erez</au><au>Rotin, Daniil</au><au>Grinshpun, Albert</au><au>Kamer, Iris</au><au>Bar, Jair</au><au>Pines, Guy</au><au>Saidian, Daniel</au><au>Bar, Ilan</au><au>Golan, Shay</au><au>Rosenbaum, Eli</au><au>Nadu, Andrei</au><au>Ben-Ami, Eytan</au><au>Weitzen, Rony</au><au>Nechushtan, Hovav</au><au>Golan, Talia</au><au>Brenner, Baruch</au><au>Nissan, Aviram</au><au>Margalit, Ofer</au><au>Hershkovitz, Dov</au><au>Lahat, Guy</au><au>Straussman, Ravid</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer</atitle><jtitle>Nature cancer</jtitle><addtitle>Nat Cancer</addtitle><date>2022-02-01</date><risdate>2022</risdate><volume>3</volume><issue>2</issue><spage>219</spage><epage>231</epage><pages>219-231</pages><issn>2662-1347</issn><eissn>2662-1347</eissn><abstract>Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRAS
mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.</abstract><cop>England</cop><pmid>35145327</pmid><doi>10.1038/s43018-021-00325-2</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9205-5820</orcidid><orcidid>https://orcid.org/0000-0002-9476-329X</orcidid><orcidid>https://orcid.org/0000-0002-3351-5719</orcidid><orcidid>https://orcid.org/0000-0003-1639-4684</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2662-1347 |
| ispartof | Nature cancer, 2022-02, Vol.3 (2), p.219-231 |
| issn | 2662-1347 2662-1347 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2628295164 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Cell Line, Tumor Cell Proliferation Colorectal Neoplasms - drug therapy Humans Mitogen-Activated Protein Kinase Kinases Mutation Tumor Microenvironment |
| title | Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-15T18%3A01%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ex%20vivo%20organotypic%20cultures%20for%20synergistic%20therapy%20prioritization%20identify%20patient-specific%20responses%20to%20combined%20MEK%20and%20Src%20inhibition%20in%20colorectal%20cancer&rft.jtitle=Nature%20cancer&rft.au=Gavert,%20Nancy&rft.date=2022-02-01&rft.volume=3&rft.issue=2&rft.spage=219&rft.epage=231&rft.pages=219-231&rft.issn=2662-1347&rft.eissn=2662-1347&rft_id=info:doi/10.1038/s43018-021-00325-2&rft_dat=%3Cproquest_cross%3E2628295164%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2628295164&rft_id=info:pmid/35145327&rfr_iscdi=true |