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Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1
Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype...
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Published in: | Cell reports. Medicine 2023-11, Vol.4 (11), p.101282, Article 101282 |
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creator | Li, Yixiang Mahadevan, Navin R Duplaquet, Leslie Hong, Deli Durmaz, Yavuz T Jones, Kristen L Cho, Hyeonseo Morrow, Murry Protti, Andrea Poitras, Michael J Springer, Benjamin F Bronson, Roderick T Gong, Xueqian Hui, Yu-Hua Du, Jian Southard, Jackson Thai, Tran Li, Shuqiang Lizotte, Patrick H Gokhale, Prafulla C Nguyen, Quang-De Oser, Matthew G |
description | Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition. |
doi_str_mv | 10.1016/j.xcrm.2023.101282 |
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A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.</description><identifier>ISSN: 2666-3791</identifier><identifier>EISSN: 2666-3791</identifier><identifier>DOI: 10.1016/j.xcrm.2023.101282</identifier><identifier>PMID: 37992688</identifier><language>eng</language><publisher>United States: Elsevier</publisher><subject>Animals ; Aurora Kinase A - genetics ; Aurora Kinase A - therapeutic use ; B7-H1 Antigen - genetics ; Humans ; Interferons - genetics ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Mice ; Mitosis ; Small Cell Lung Carcinoma - drug therapy ; Small Cell Lung Carcinoma - genetics ; Small Cell Lung Carcinoma - pathology</subject><ispartof>Cell reports. Medicine, 2023-11, Vol.4 (11), p.101282, Article 101282</ispartof><rights>Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>2023 The Author(s) 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c403t-9c2af0bd86def727b373a14e1bf829342b4df650cc2ce5aed82e7cdb08a6441d3</citedby><cites>FETCH-LOGICAL-c403t-9c2af0bd86def727b373a14e1bf829342b4df650cc2ce5aed82e7cdb08a6441d3</cites><orcidid>0000-0003-2047-0969</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/PMC10694667/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694667/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37992688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yixiang</creatorcontrib><creatorcontrib>Mahadevan, Navin R</creatorcontrib><creatorcontrib>Duplaquet, Leslie</creatorcontrib><creatorcontrib>Hong, Deli</creatorcontrib><creatorcontrib>Durmaz, Yavuz T</creatorcontrib><creatorcontrib>Jones, Kristen L</creatorcontrib><creatorcontrib>Cho, Hyeonseo</creatorcontrib><creatorcontrib>Morrow, Murry</creatorcontrib><creatorcontrib>Protti, Andrea</creatorcontrib><creatorcontrib>Poitras, Michael J</creatorcontrib><creatorcontrib>Springer, Benjamin F</creatorcontrib><creatorcontrib>Bronson, Roderick T</creatorcontrib><creatorcontrib>Gong, Xueqian</creatorcontrib><creatorcontrib>Hui, Yu-Hua</creatorcontrib><creatorcontrib>Du, Jian</creatorcontrib><creatorcontrib>Southard, Jackson</creatorcontrib><creatorcontrib>Thai, Tran</creatorcontrib><creatorcontrib>Li, Shuqiang</creatorcontrib><creatorcontrib>Lizotte, Patrick H</creatorcontrib><creatorcontrib>Gokhale, Prafulla C</creatorcontrib><creatorcontrib>Nguyen, Quang-De</creatorcontrib><creatorcontrib>Oser, Matthew G</creatorcontrib><title>Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1</title><title>Cell reports. Medicine</title><addtitle>Cell Rep Med</addtitle><description>Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.</description><subject>Animals</subject><subject>Aurora Kinase A - genetics</subject><subject>Aurora Kinase A - therapeutic use</subject><subject>B7-H1 Antigen - genetics</subject><subject>Humans</subject><subject>Interferons - genetics</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Mitosis</subject><subject>Small Cell Lung Carcinoma - drug therapy</subject><subject>Small Cell Lung Carcinoma - genetics</subject><subject>Small Cell Lung Carcinoma - pathology</subject><issn>2666-3791</issn><issn>2666-3791</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpVUc2OFCEYJEbjbtZ9AQ-Go5ce-RuaPpnJqKvJJJqoZ0LD1zOM3TAC7c9T7CtLO-tmPVGpr6o-oBB6TsmKEipfHVe_bJpWjDC-EEyxR-iSSSkb3nb08QN8ga5zPhJC2JpSxclTdFHpjkmlLtHtZk4xGbzB33wwGbAPB9_74mOo0M0WMjbWztM8mr9kHPDn7W6LyzzFhC2MY65CPPkSs8_4py8HnCCXmMDVQYE0QKq-7PfBjD7scYmVtwmWbVV5iqGCSn560-zoM_RkMGOG67vzCn199_bL9n2z-3jzYbvZNVYQXprOMjOQ3inpYGhZ2_OWGyqA9oNiHResF26Qa2Its7A24BSD1rqeKCOFoI5fodfn3NPcT-AshJLMqE_JTyb91tF4_f8k-IPexx-aEtkJKdua8PIuIcXvc32xnnxe_sMEiHPWTHWsE2otRJWys9SmmHOC4X4PJXppUx_10qZe2tTnNqvpxcMb3lv-dcf_ABBmoJA</recordid><startdate>20231121</startdate><enddate>20231121</enddate><creator>Li, Yixiang</creator><creator>Mahadevan, Navin R</creator><creator>Duplaquet, Leslie</creator><creator>Hong, Deli</creator><creator>Durmaz, Yavuz T</creator><creator>Jones, Kristen L</creator><creator>Cho, Hyeonseo</creator><creator>Morrow, Murry</creator><creator>Protti, Andrea</creator><creator>Poitras, Michael J</creator><creator>Springer, Benjamin F</creator><creator>Bronson, Roderick T</creator><creator>Gong, Xueqian</creator><creator>Hui, Yu-Hua</creator><creator>Du, Jian</creator><creator>Southard, Jackson</creator><creator>Thai, Tran</creator><creator>Li, Shuqiang</creator><creator>Lizotte, Patrick H</creator><creator>Gokhale, Prafulla C</creator><creator>Nguyen, Quang-De</creator><creator>Oser, Matthew G</creator><general>Elsevier</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2047-0969</orcidid></search><sort><creationdate>20231121</creationdate><title>Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1</title><author>Li, Yixiang ; Mahadevan, Navin R ; Duplaquet, Leslie ; Hong, Deli ; Durmaz, Yavuz T ; Jones, Kristen L ; Cho, Hyeonseo ; Morrow, Murry ; Protti, Andrea ; Poitras, Michael J ; Springer, Benjamin F ; Bronson, Roderick T ; Gong, Xueqian ; Hui, Yu-Hua ; Du, Jian ; Southard, Jackson ; Thai, Tran ; Li, Shuqiang ; Lizotte, Patrick H ; Gokhale, Prafulla C ; Nguyen, Quang-De ; Oser, Matthew G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c403t-9c2af0bd86def727b373a14e1bf829342b4df650cc2ce5aed82e7cdb08a6441d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Aurora Kinase A - genetics</topic><topic>Aurora Kinase A - therapeutic use</topic><topic>B7-H1 Antigen - genetics</topic><topic>Humans</topic><topic>Interferons - genetics</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>Mitosis</topic><topic>Small Cell Lung Carcinoma - drug therapy</topic><topic>Small Cell Lung Carcinoma - genetics</topic><topic>Small Cell Lung Carcinoma - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yixiang</creatorcontrib><creatorcontrib>Mahadevan, Navin R</creatorcontrib><creatorcontrib>Duplaquet, Leslie</creatorcontrib><creatorcontrib>Hong, Deli</creatorcontrib><creatorcontrib>Durmaz, Yavuz T</creatorcontrib><creatorcontrib>Jones, Kristen L</creatorcontrib><creatorcontrib>Cho, Hyeonseo</creatorcontrib><creatorcontrib>Morrow, Murry</creatorcontrib><creatorcontrib>Protti, Andrea</creatorcontrib><creatorcontrib>Poitras, Michael J</creatorcontrib><creatorcontrib>Springer, Benjamin F</creatorcontrib><creatorcontrib>Bronson, Roderick T</creatorcontrib><creatorcontrib>Gong, Xueqian</creatorcontrib><creatorcontrib>Hui, Yu-Hua</creatorcontrib><creatorcontrib>Du, Jian</creatorcontrib><creatorcontrib>Southard, Jackson</creatorcontrib><creatorcontrib>Thai, Tran</creatorcontrib><creatorcontrib>Li, Shuqiang</creatorcontrib><creatorcontrib>Lizotte, Patrick H</creatorcontrib><creatorcontrib>Gokhale, Prafulla C</creatorcontrib><creatorcontrib>Nguyen, Quang-De</creatorcontrib><creatorcontrib>Oser, Matthew G</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell reports. Medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yixiang</au><au>Mahadevan, Navin R</au><au>Duplaquet, Leslie</au><au>Hong, Deli</au><au>Durmaz, Yavuz T</au><au>Jones, Kristen L</au><au>Cho, Hyeonseo</au><au>Morrow, Murry</au><au>Protti, Andrea</au><au>Poitras, Michael J</au><au>Springer, Benjamin F</au><au>Bronson, Roderick T</au><au>Gong, Xueqian</au><au>Hui, Yu-Hua</au><au>Du, Jian</au><au>Southard, Jackson</au><au>Thai, Tran</au><au>Li, Shuqiang</au><au>Lizotte, Patrick H</au><au>Gokhale, Prafulla C</au><au>Nguyen, Quang-De</au><au>Oser, Matthew G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1</atitle><jtitle>Cell reports. Medicine</jtitle><addtitle>Cell Rep Med</addtitle><date>2023-11-21</date><risdate>2023</risdate><volume>4</volume><issue>11</issue><spage>101282</spage><pages>101282-</pages><artnum>101282</artnum><issn>2666-3791</issn><eissn>2666-3791</eissn><abstract>Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.</abstract><cop>United States</cop><pub>Elsevier</pub><pmid>37992688</pmid><doi>10.1016/j.xcrm.2023.101282</doi><orcidid>https://orcid.org/0000-0003-2047-0969</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Aurora Kinase A - genetics Aurora Kinase A - therapeutic use B7-H1 Antigen - genetics Humans Interferons - genetics Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - pathology Mice Mitosis Small Cell Lung Carcinoma - drug therapy Small Cell Lung Carcinoma - genetics Small Cell Lung Carcinoma - pathology |
title | Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1 |
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