A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response
Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction...
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| Veröffentlicht in: | Oncogene 2022-06, Vol.41 (23), p.3289-3297 |
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| creator | Kim, Ji Young Cho, Tae-Min Park, Jung Min Park, Soeun Park, Minsu Nam, Kee Dal Ko, Dongmi Seo, Juyeon Kim, Seongjae Jung, Eunsun Farrand, Lee Nguyen, Cong-Truong Hoang, Van-Hai Thanh La, Minh Ann, Jihyae Nam, Gibeom Park, Hyun-Ju Lee, Jeewoo Kim, Yoon-Jae Seo, Jae Hong |
| description | Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR. |
| doi_str_mv | 10.1038/s41388-022-02269-y |
| format | Article |
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Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-022-02269-y</identifier><identifier>PMID: 35501463</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 13/31 ; 13/51 ; 14/19 ; 14/5 ; 631/67/1347 ; 631/80/82/23 ; 64/60 ; 82/29 ; 82/80 ; AKT protein ; Angiogenesis ; Antineoplastic Agents - pharmacology ; Apoptosis ; Bioluminescence ; Breast cancer ; Brief Communication ; Cell Biology ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell Proliferation ; Cytotoxicity ; Drug resistance ; Experiments ; Heat shock proteins ; Heat-Shock Response ; HSP90 Heat-Shock Proteins - metabolism ; Hsp90 protein ; Human Genetics ; Humans ; Internal Medicine ; Janus kinase 2 ; Laboratory animals ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Oncology ; Penicillin ; Pharmacy ; Signal transduction ; Software ; Stat3 protein ; Stem cells ; Toxicity ; Triple Negative Breast Neoplasms - pathology ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Oncogene, 2022-06, Vol.41 (23), p.3289-3297</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://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><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-2263847979f0ab02ec661b13d532f94e8df2655f5614b6a0dbcc2e25abc841e3</citedby><cites>FETCH-LOGICAL-c474t-2263847979f0ab02ec661b13d532f94e8df2655f5614b6a0dbcc2e25abc841e3</cites><orcidid>0000-0002-7832-6719 ; 0000-0002-7363-6419 ; 0000-0002-1675-8604 ; 0000-0001-5378-9947 ; 0000-0001-7462-9598 ; 0000-0002-5043-8014</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/s41388-022-02269-y$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-022-02269-y$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35501463$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Ji Young</creatorcontrib><creatorcontrib>Cho, Tae-Min</creatorcontrib><creatorcontrib>Park, Jung Min</creatorcontrib><creatorcontrib>Park, Soeun</creatorcontrib><creatorcontrib>Park, Minsu</creatorcontrib><creatorcontrib>Nam, Kee Dal</creatorcontrib><creatorcontrib>Ko, Dongmi</creatorcontrib><creatorcontrib>Seo, Juyeon</creatorcontrib><creatorcontrib>Kim, Seongjae</creatorcontrib><creatorcontrib>Jung, Eunsun</creatorcontrib><creatorcontrib>Farrand, Lee</creatorcontrib><creatorcontrib>Nguyen, Cong-Truong</creatorcontrib><creatorcontrib>Hoang, Van-Hai</creatorcontrib><creatorcontrib>Thanh La, Minh</creatorcontrib><creatorcontrib>Ann, Jihyae</creatorcontrib><creatorcontrib>Nam, Gibeom</creatorcontrib><creatorcontrib>Park, Hyun-Ju</creatorcontrib><creatorcontrib>Lee, Jeewoo</creatorcontrib><creatorcontrib>Kim, Yoon-Jae</creatorcontrib><creatorcontrib>Seo, Jae Hong</creatorcontrib><title>A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.</description><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>14/19</subject><subject>14/5</subject><subject>631/67/1347</subject><subject>631/80/82/23</subject><subject>64/60</subject><subject>82/29</subject><subject>82/80</subject><subject>AKT protein</subject><subject>Angiogenesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Bioluminescence</subject><subject>Breast cancer</subject><subject>Brief Communication</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cytotoxicity</subject><subject>Drug resistance</subject><subject>Experiments</subject><subject>Heat shock proteins</subject><subject>Heat-Shock Response</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Hsp90 protein</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Janus kinase 2</subject><subject>Laboratory animals</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Oncology</subject><subject>Penicillin</subject><subject>Pharmacy</subject><subject>Signal transduction</subject><subject>Software</subject><subject>Stat3 protein</subject><subject>Stem cells</subject><subject>Toxicity</subject><subject>Triple Negative Breast Neoplasms - 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Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. 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| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2022-06, Vol.41 (23), p.3289-3297 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9166677 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 13/2 13/31 13/51 14/19 14/5 631/67/1347 631/80/82/23 64/60 82/29 82/80 AKT protein Angiogenesis Antineoplastic Agents - pharmacology Apoptosis Bioluminescence Breast cancer Brief Communication Cell Biology Cell cycle Cell growth Cell Line, Tumor Cell Proliferation Cytotoxicity Drug resistance Experiments Heat shock proteins Heat-Shock Response HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Human Genetics Humans Internal Medicine Janus kinase 2 Laboratory animals Medicine Medicine & Public Health Metastases Metastasis Oncology Penicillin Pharmacy Signal transduction Software Stat3 protein Stem cells Toxicity Triple Negative Breast Neoplasms - pathology Tumors Xenograft Model Antitumor Assays |
| title | A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T03%3A36%3A35IST&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=A%20novel%20HSP90%20inhibitor%20SL-145%20suppresses%20metastatic%20triple-negative%20breast%20cancer%20without%20triggering%20the%20heat%20shock%20response&rft.jtitle=Oncogene&rft.au=Kim,%20Ji%20Young&rft.date=2022-06-03&rft.volume=41&rft.issue=23&rft.spage=3289&rft.epage=3297&rft.pages=3289-3297&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-022-02269-y&rft_dat=%3Cproquest_pubme%3E2659228781%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=2672839221&rft_id=info:pmid/35501463&rfr_iscdi=true |