FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy
Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor...
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| Veröffentlicht in: | International journal of molecular sciences 2019-09, Vol.20 (18), p.4563 |
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| creator | Darwis, Narisa Dewi Maulany Nachankar, Ankita Sasaki, Yasushi Matsui, Toshiaki Noda, Shin-Ei Murata, Kazutoshi Tamaki, Tomoaki Ando, Ken Okonogi, Noriyuki Shiba, Shintaro Irie, Daisuke Kaminuma, Takuya Kumazawa, Takuya Anakura, Mai Yamashita, Souichi Hirakawa, Takashi Kakoti, Sangeeta Hirota, Yuka Tokino, Takashi Iwase, Akira Ohno, Tatsuya Shibata, Atsushi Oike, Takahiro Nakano, Takashi |
| description | Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in
and
in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts. |
| doi_str_mv | 10.3390/ijms20184563 |
| format | Article |
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and
in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20184563</identifier><identifier>PMID: 31540114</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>A549 Cells ; Apoptosis ; Biopsy ; Bladder cancer ; Carbon ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - radiotherapy ; Cervical cancer ; Cervix ; Communication ; Cytotoxicity ; Experiments ; Female ; Fibroblast growth factor receptors ; Gastric cancer ; Gene Ontology ; Heavy Ion Radiotherapy ; High-Throughput Nucleotide Sequencing ; Humans ; Indazoles - pharmacology ; Kinases ; Lung cancer ; Middle Aged ; Multiple myeloma ; Mutation ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - genetics ; Patients ; Phosphorylation ; Pilot Projects ; Radiation therapy ; Radiosensitization ; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 3 - genetics ; Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 4 - genetics ; Signal Transduction ; Studies ; Therapeutic applications ; Tumor cell lines ; Tumors ; Uterine cancer ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - radiotherapy ; Uterus ; Xenografts ; Xenotransplantation</subject><ispartof>International journal of molecular sciences, 2019-09, Vol.20 (18), p.4563</ispartof><rights>2019. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-c79d9d2dd7b7e033f4fa040c2b90f87ed1b47ba7124876d1f08be1a8b109ebf63</citedby><cites>FETCH-LOGICAL-c478t-c79d9d2dd7b7e033f4fa040c2b90f87ed1b47ba7124876d1f08be1a8b109ebf63</cites><orcidid>0000-0002-3500-8059 ; 0000-0001-8912-6977</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770837/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770837/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31540114$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Darwis, Narisa Dewi Maulany</creatorcontrib><creatorcontrib>Nachankar, Ankita</creatorcontrib><creatorcontrib>Sasaki, Yasushi</creatorcontrib><creatorcontrib>Matsui, Toshiaki</creatorcontrib><creatorcontrib>Noda, Shin-Ei</creatorcontrib><creatorcontrib>Murata, Kazutoshi</creatorcontrib><creatorcontrib>Tamaki, Tomoaki</creatorcontrib><creatorcontrib>Ando, Ken</creatorcontrib><creatorcontrib>Okonogi, Noriyuki</creatorcontrib><creatorcontrib>Shiba, Shintaro</creatorcontrib><creatorcontrib>Irie, Daisuke</creatorcontrib><creatorcontrib>Kaminuma, Takuya</creatorcontrib><creatorcontrib>Kumazawa, Takuya</creatorcontrib><creatorcontrib>Anakura, Mai</creatorcontrib><creatorcontrib>Yamashita, Souichi</creatorcontrib><creatorcontrib>Hirakawa, Takashi</creatorcontrib><creatorcontrib>Kakoti, Sangeeta</creatorcontrib><creatorcontrib>Hirota, Yuka</creatorcontrib><creatorcontrib>Tokino, Takashi</creatorcontrib><creatorcontrib>Iwase, Akira</creatorcontrib><creatorcontrib>Ohno, Tatsuya</creatorcontrib><creatorcontrib>Shibata, Atsushi</creatorcontrib><creatorcontrib>Oike, Takahiro</creatorcontrib><creatorcontrib>Nakano, Takashi</creatorcontrib><title>FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in
and
in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.</description><subject>A549 Cells</subject><subject>Apoptosis</subject><subject>Biopsy</subject><subject>Bladder cancer</subject><subject>Carbon</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - radiotherapy</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Communication</subject><subject>Cytotoxicity</subject><subject>Experiments</subject><subject>Female</subject><subject>Fibroblast growth factor receptors</subject><subject>Gastric cancer</subject><subject>Gene Ontology</subject><subject>Heavy Ion Radiotherapy</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Indazoles - pharmacology</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Middle Aged</subject><subject>Multiple myeloma</subject><subject>Mutation</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Patients</subject><subject>Phosphorylation</subject><subject>Pilot Projects</subject><subject>Radiation therapy</subject><subject>Radiosensitization</subject><subject>Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors</subject><subject>Receptor, Fibroblast Growth Factor, Type 3 - genetics</subject><subject>Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors</subject><subject>Receptor, Fibroblast Growth Factor, Type 4 - genetics</subject><subject>Signal Transduction</subject><subject>Studies</subject><subject>Therapeutic applications</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Uterine cancer</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - radiotherapy</subject><subject>Uterus</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkd9rFDEQx4NYbK2--SwBX_rg1cmP3WRfBDm8WigI5_kcJpvsNcfe5kyyQv_7praW04cwIfOZb2bmS8g7BpdCdPAp7PaZA9OyacULcsYk5wuAVr08up-S1znvALjgTfeKnArWSGBMnhFcXa3W9EfYTjiGaUsxU6RLnFxwWDzd3PqEBz-X0NMNpq0vdIjpAeh9ynTtc8gFp0JLrI_Jxole17NGF2L5U3v3hpwMOGb_9imek5-rr5vlt8XN96vr5ZebRS-VLoteda5z3DlllQchBjkgSOi57WDQyjtmpbKoGJdatY4NoK1nqC2DztuhFefk86PuYbZ773o_lYSjOaSwx3RnIgbzb2YKt2Ybf5tWKdBCVYGLJ4EUf80-F7MPuffjiJOPczacd039G1pe0Q__obs4p7rCSgkhNJeN0JX6-Ej1Keac_PDcDAPz4J059q7i748HeIb_miXuAUzulaA</recordid><startdate>20190914</startdate><enddate>20190914</enddate><creator>Darwis, Narisa Dewi Maulany</creator><creator>Nachankar, Ankita</creator><creator>Sasaki, Yasushi</creator><creator>Matsui, Toshiaki</creator><creator>Noda, Shin-Ei</creator><creator>Murata, Kazutoshi</creator><creator>Tamaki, Tomoaki</creator><creator>Ando, Ken</creator><creator>Okonogi, Noriyuki</creator><creator>Shiba, Shintaro</creator><creator>Irie, Daisuke</creator><creator>Kaminuma, Takuya</creator><creator>Kumazawa, Takuya</creator><creator>Anakura, Mai</creator><creator>Yamashita, Souichi</creator><creator>Hirakawa, Takashi</creator><creator>Kakoti, Sangeeta</creator><creator>Hirota, Yuka</creator><creator>Tokino, Takashi</creator><creator>Iwase, Akira</creator><creator>Ohno, Tatsuya</creator><creator>Shibata, Atsushi</creator><creator>Oike, Takahiro</creator><creator>Nakano, Takashi</creator><general>MDPI AG</general><general>MDPI</general><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3500-8059</orcidid><orcidid>https://orcid.org/0000-0001-8912-6977</orcidid></search><sort><creationdate>20190914</creationdate><title>FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy</title><author>Darwis, Narisa Dewi Maulany ; Nachankar, Ankita ; Sasaki, Yasushi ; Matsui, Toshiaki ; Noda, Shin-Ei ; Murata, Kazutoshi ; Tamaki, Tomoaki ; Ando, Ken ; Okonogi, Noriyuki ; Shiba, Shintaro ; Irie, Daisuke ; Kaminuma, Takuya ; Kumazawa, Takuya ; Anakura, Mai ; Yamashita, Souichi ; Hirakawa, Takashi ; Kakoti, Sangeeta ; Hirota, Yuka ; Tokino, Takashi ; Iwase, Akira ; Ohno, Tatsuya ; Shibata, Atsushi ; Oike, Takahiro ; Nakano, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-c79d9d2dd7b7e033f4fa040c2b90f87ed1b47ba7124876d1f08be1a8b109ebf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>A549 Cells</topic><topic>Apoptosis</topic><topic>Biopsy</topic><topic>Bladder cancer</topic><topic>Carbon</topic><topic>Carcinoma, Squamous Cell - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Darwis, Narisa Dewi Maulany</au><au>Nachankar, Ankita</au><au>Sasaki, Yasushi</au><au>Matsui, Toshiaki</au><au>Noda, Shin-Ei</au><au>Murata, Kazutoshi</au><au>Tamaki, Tomoaki</au><au>Ando, Ken</au><au>Okonogi, Noriyuki</au><au>Shiba, Shintaro</au><au>Irie, Daisuke</au><au>Kaminuma, Takuya</au><au>Kumazawa, Takuya</au><au>Anakura, Mai</au><au>Yamashita, Souichi</au><au>Hirakawa, Takashi</au><au>Kakoti, Sangeeta</au><au>Hirota, Yuka</au><au>Tokino, Takashi</au><au>Iwase, Akira</au><au>Ohno, Tatsuya</au><au>Shibata, Atsushi</au><au>Oike, Takahiro</au><au>Nakano, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-09-14</date><risdate>2019</risdate><volume>20</volume><issue>18</issue><spage>4563</spage><pages>4563-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in
and
in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31540114</pmid><doi>10.3390/ijms20184563</doi><orcidid>https://orcid.org/0000-0002-3500-8059</orcidid><orcidid>https://orcid.org/0000-0001-8912-6977</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2019-09, Vol.20 (18), p.4563 |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6770837 |
| source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | A549 Cells Apoptosis Biopsy Bladder cancer Carbon Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - radiotherapy Cervical cancer Cervix Communication Cytotoxicity Experiments Female Fibroblast growth factor receptors Gastric cancer Gene Ontology Heavy Ion Radiotherapy High-Throughput Nucleotide Sequencing Humans Indazoles - pharmacology Kinases Lung cancer Middle Aged Multiple myeloma Mutation Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - genetics Patients Phosphorylation Pilot Projects Radiation therapy Radiosensitization Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 3 - genetics Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 4 - genetics Signal Transduction Studies Therapeutic applications Tumor cell lines Tumors Uterine cancer Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - radiotherapy Uterus Xenografts Xenotransplantation |
| title | FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-26T12%3A49%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=FGFR%20Signaling%20as%20a%20Candidate%20Therapeutic%20Target%20for%20Cancers%20Resistant%20to%20Carbon%20Ion%20Radiotherapy&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Darwis,%20Narisa%20Dewi%20Maulany&rft.date=2019-09-14&rft.volume=20&rft.issue=18&rft.spage=4563&rft.pages=4563-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms20184563&rft_dat=%3Cproquest_pubme%3E2333824538%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2333824538&rft_id=info:pmid/31540114&rfr_iscdi=true |