Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer
Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP‐based chemotherapy is the first‐line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported...
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| Veröffentlicht in: | Cancer science 2021-09, Vol.112 (9), p.3669-3681 |
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| creator | Murakami, Kaoru Kita, Yuki Sakatani, Toru Hamada, Akihiro Mizuno, Kei Nakamura, Kenji Takada, Hideaki Matsumoto, Keiyu Sano, Takeshi Goto, Takayuki Akamatsu, Shusuke Saito, Ryoichi Tsuruyama, Tatsuaki Ogawa, Osamu Kobayashi, Takashi |
| description | Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP‐based chemotherapy is the first‐line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK‐1775, a WEE1 inhibitor also known as AZD‐1775, blocked proliferation of UC cell lines in a dose‐dependent manner irrespective of TP53 status. MK‐1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53‐mutant UC cells but not in TP53‐WT cells. Knocking down TP53 in TP53‐WT cells induced synergism of MK‐1775 and CDDP. In UMUC3 cell xenografts and two patient‐derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD‐1775 combined with CDDP suppressed tumor growth inducing both M‐phase entry and apoptosis, whereas AZD‐1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.
WEE1 inhibitor and cisplatin (CDDP) in combination was significantly more effective than the single treatments. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP. |
| doi_str_mv | 10.1111/cas.15051 |
| format | Article |
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WEE1 inhibitor and cisplatin (CDDP) in combination was significantly more effective than the single treatments. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15051</identifier><identifier>PMID: 34212455</identifier><language>eng</language><publisher>Tokyo: John Wiley & Sons, Inc</publisher><subject>Antimitotic agents ; Antineoplastic agents ; Antitumor activity ; Apoptosis ; Bladder cancer ; Cancer ; Cancer therapies ; Cell culture ; Cell cycle ; Cell proliferation ; Chemoresistance ; Chemotherapy ; Cisplatin ; Clinical trials ; Cyclin-dependent kinases ; Disease susceptibility ; DNA damage ; DNA repair ; Gene expression ; Genotoxicity ; Health aspects ; Kinases ; MDM2 protein ; Original ; p53 ; Patients ; Spheroids ; Tumor proteins ; Tumors ; Urothelial cancer ; WEE1 ; Xenografts</subject><ispartof>Cancer science, 2021-09, Vol.112 (9), p.3669-3681</ispartof><rights>2021 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>COPYRIGHT 2021 John Wiley & Sons, Inc.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by-nc-nd/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-c5551-26b09a0e1692d90f3cd316d1d6c5c07b3fabb881b46c9e45018237639008e3563</citedby><cites>FETCH-LOGICAL-c5551-26b09a0e1692d90f3cd316d1d6c5c07b3fabb881b46c9e45018237639008e3563</cites><orcidid>0000-0002-4226-3867 ; 0000-0003-1069-2816</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/PMC8409401/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409401/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids></links><search><creatorcontrib>Murakami, Kaoru</creatorcontrib><creatorcontrib>Kita, Yuki</creatorcontrib><creatorcontrib>Sakatani, Toru</creatorcontrib><creatorcontrib>Hamada, Akihiro</creatorcontrib><creatorcontrib>Mizuno, Kei</creatorcontrib><creatorcontrib>Nakamura, Kenji</creatorcontrib><creatorcontrib>Takada, Hideaki</creatorcontrib><creatorcontrib>Matsumoto, Keiyu</creatorcontrib><creatorcontrib>Sano, Takeshi</creatorcontrib><creatorcontrib>Goto, Takayuki</creatorcontrib><creatorcontrib>Akamatsu, Shusuke</creatorcontrib><creatorcontrib>Saito, Ryoichi</creatorcontrib><creatorcontrib>Tsuruyama, Tatsuaki</creatorcontrib><creatorcontrib>Ogawa, Osamu</creatorcontrib><creatorcontrib>Kobayashi, Takashi</creatorcontrib><title>Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer</title><title>Cancer science</title><description>Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP‐based chemotherapy is the first‐line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK‐1775, a WEE1 inhibitor also known as AZD‐1775, blocked proliferation of UC cell lines in a dose‐dependent manner irrespective of TP53 status. MK‐1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53‐mutant UC cells but not in TP53‐WT cells. Knocking down TP53 in TP53‐WT cells induced synergism of MK‐1775 and CDDP. In UMUC3 cell xenografts and two patient‐derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD‐1775 combined with CDDP suppressed tumor growth inducing both M‐phase entry and apoptosis, whereas AZD‐1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.
WEE1 inhibitor and cisplatin (CDDP) in combination was significantly more effective than the single treatments. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP.</description><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Bladder cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Clinical trials</subject><subject>Cyclin-dependent kinases</subject><subject>Disease susceptibility</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Gene expression</subject><subject>Genotoxicity</subject><subject>Health aspects</subject><subject>Kinases</subject><subject>MDM2 protein</subject><subject>Original</subject><subject>p53</subject><subject>Patients</subject><subject>Spheroids</subject><subject>Tumor proteins</subject><subject>Tumors</subject><subject>Urothelial cancer</subject><subject>WEE1</subject><subject>Xenografts</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kkuLFDEUhQtRnHF04T8IuNFF9dxUXpWN0DTtAwZcqLgMqVQynTGVtEmVQ_9709ODMqLJIje53znhwmmalxhWuK5Lo8sKM2D4UXOOCZWtAOCP72rRSiDdWfOslBsAwqmkT5szQjvcUcbOG7eOs5-XKWVknbNmRsmhb9stRkNI5rseLdIFTSmmeWez3h9QJX1EJk2Dj3r2KaJbP--Q8WUf6j0eu0s-4sHrgIyOxubnzROnQ7Ev7s-L5uu77ZfNh_bq0_uPm_VVaxhjuO34AFKDxVx2owRHzEgwH_HIDTMgBuL0MPQ9Hig30lIGuO-I4EQC9JYwTi6atyff_TJMdjQ2zlkHtc9-0vmgkvbqYSf6nbpOP1VPQVLA1eD1vUFOPxZbZjX5YmwIOtq0FNUx2lMMHSYVffUXepOWHOt4leJCCiFl_4e61sEqH12q_5qjqVoLDIL2XIpKrf5B1T3ayZsUrfP1_YHgzUlgciolW_d7RgzqGApVQ6HuQlHZyxN7W00O_wfVZv35pPgFp1y1VQ</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Murakami, Kaoru</creator><creator>Kita, Yuki</creator><creator>Sakatani, Toru</creator><creator>Hamada, Akihiro</creator><creator>Mizuno, Kei</creator><creator>Nakamura, Kenji</creator><creator>Takada, Hideaki</creator><creator>Matsumoto, Keiyu</creator><creator>Sano, Takeshi</creator><creator>Goto, Takayuki</creator><creator>Akamatsu, Shusuke</creator><creator>Saito, Ryoichi</creator><creator>Tsuruyama, Tatsuaki</creator><creator>Ogawa, Osamu</creator><creator>Kobayashi, Takashi</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4226-3867</orcidid><orcidid>https://orcid.org/0000-0003-1069-2816</orcidid></search><sort><creationdate>202109</creationdate><title>Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer</title><author>Murakami, Kaoru ; Kita, Yuki ; Sakatani, Toru ; Hamada, Akihiro ; Mizuno, Kei ; Nakamura, Kenji ; Takada, Hideaki ; Matsumoto, Keiyu ; Sano, Takeshi ; Goto, Takayuki ; Akamatsu, Shusuke ; Saito, Ryoichi ; Tsuruyama, Tatsuaki ; Ogawa, Osamu ; Kobayashi, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5551-26b09a0e1692d90f3cd316d1d6c5c07b3fabb881b46c9e45018237639008e3563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Bladder cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell culture</topic><topic>Cell cycle</topic><topic>Cell proliferation</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Clinical trials</topic><topic>Cyclin-dependent kinases</topic><topic>Disease susceptibility</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Gene expression</topic><topic>Genotoxicity</topic><topic>Health aspects</topic><topic>Kinases</topic><topic>MDM2 protein</topic><topic>Original</topic><topic>p53</topic><topic>Patients</topic><topic>Spheroids</topic><topic>Tumor proteins</topic><topic>Tumors</topic><topic>Urothelial cancer</topic><topic>WEE1</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murakami, Kaoru</creatorcontrib><creatorcontrib>Kita, Yuki</creatorcontrib><creatorcontrib>Sakatani, Toru</creatorcontrib><creatorcontrib>Hamada, Akihiro</creatorcontrib><creatorcontrib>Mizuno, Kei</creatorcontrib><creatorcontrib>Nakamura, Kenji</creatorcontrib><creatorcontrib>Takada, Hideaki</creatorcontrib><creatorcontrib>Matsumoto, Keiyu</creatorcontrib><creatorcontrib>Sano, Takeshi</creatorcontrib><creatorcontrib>Goto, Takayuki</creatorcontrib><creatorcontrib>Akamatsu, Shusuke</creatorcontrib><creatorcontrib>Saito, Ryoichi</creatorcontrib><creatorcontrib>Tsuruyama, Tatsuaki</creatorcontrib><creatorcontrib>Ogawa, Osamu</creatorcontrib><creatorcontrib>Kobayashi, Takashi</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Murakami, Kaoru</au><au>Kita, Yuki</au><au>Sakatani, Toru</au><au>Hamada, Akihiro</au><au>Mizuno, Kei</au><au>Nakamura, Kenji</au><au>Takada, Hideaki</au><au>Matsumoto, Keiyu</au><au>Sano, Takeshi</au><au>Goto, Takayuki</au><au>Akamatsu, Shusuke</au><au>Saito, Ryoichi</au><au>Tsuruyama, Tatsuaki</au><au>Ogawa, Osamu</au><au>Kobayashi, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer</atitle><jtitle>Cancer science</jtitle><date>2021-09</date><risdate>2021</risdate><volume>112</volume><issue>9</issue><spage>3669</spage><epage>3681</epage><pages>3669-3681</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP‐based chemotherapy is the first‐line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK‐1775, a WEE1 inhibitor also known as AZD‐1775, blocked proliferation of UC cell lines in a dose‐dependent manner irrespective of TP53 status. MK‐1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53‐mutant UC cells but not in TP53‐WT cells. Knocking down TP53 in TP53‐WT cells induced synergism of MK‐1775 and CDDP. In UMUC3 cell xenografts and two patient‐derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD‐1775 combined with CDDP suppressed tumor growth inducing both M‐phase entry and apoptosis, whereas AZD‐1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.
WEE1 inhibitor and cisplatin (CDDP) in combination was significantly more effective than the single treatments. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP.</abstract><cop>Tokyo</cop><pub>John Wiley & Sons, Inc</pub><pmid>34212455</pmid><doi>10.1111/cas.15051</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-4226-3867</orcidid><orcidid>https://orcid.org/0000-0003-1069-2816</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antimitotic agents Antineoplastic agents Antitumor activity Apoptosis Bladder cancer Cancer Cancer therapies Cell culture Cell cycle Cell proliferation Chemoresistance Chemotherapy Cisplatin Clinical trials Cyclin-dependent kinases Disease susceptibility DNA damage DNA repair Gene expression Genotoxicity Health aspects Kinases MDM2 protein Original p53 Patients Spheroids Tumor proteins Tumors Urothelial cancer WEE1 Xenografts |
| title | Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer |
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