Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer
Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spe...
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| Veröffentlicht in: | Nature cancer 2022-06, Vol.3 (6), p.710-722 |
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| creator | Shiba-Ishii, Aya Johnson, Ted W Dagogo-Jack, Ibiayi Mino-Kenudson, Mari Johnson, Theodore R Wei, Ping Weinrich, Scott L McTigue, Michele A Walcott, Makeba A Nguyen-Phuong, Linh Dionne, Kristin Acker, Adam Kiedrowski, Lesli A Do, Andrew Peterson, Jennifer L Barth, Jaimie L Yeap, Beow Y Gainor, Justin F Lin, Jessica J Yoda, Satoshi Hata, Aaron N |
| description | Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors. |
| doi_str_mv | 10.1038/s43018-022-00399-6 |
| format | Article |
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Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.</description><identifier>ISSN: 2662-1347</identifier><identifier>EISSN: 2662-1347</identifier><identifier>DOI: 10.1038/s43018-022-00399-6</identifier><identifier>PMID: 35726063</identifier><language>eng</language><publisher>England</publisher><subject>Aminopyridines ; Anaplastic Lymphoma Kinase - genetics ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Drug Resistance, Neoplasm - genetics ; Humans ; Lactams ; Lactams, Macrocyclic - pharmacology ; Lung Neoplasms - drug therapy ; Mutation ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles</subject><ispartof>Nature cancer, 2022-06, Vol.3 (6), p.710-722</ispartof><rights>2022. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-8394267871c69db596833ecbcda4c582d273a48044f5c0266661c9bf10f2234d3</citedby><cites>FETCH-LOGICAL-c402t-8394267871c69db596833ecbcda4c582d273a48044f5c0266661c9bf10f2234d3</cites><orcidid>0000-0001-8697-4081 ; 0000-0003-4201-1392 ; 0000-0001-5081-2005 ; 0000-0002-9092-2265 ; 0000-0001-7373-3916 ; 0000-0002-6127-318X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35726063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shiba-Ishii, Aya</creatorcontrib><creatorcontrib>Johnson, Ted W</creatorcontrib><creatorcontrib>Dagogo-Jack, Ibiayi</creatorcontrib><creatorcontrib>Mino-Kenudson, Mari</creatorcontrib><creatorcontrib>Johnson, Theodore R</creatorcontrib><creatorcontrib>Wei, Ping</creatorcontrib><creatorcontrib>Weinrich, Scott L</creatorcontrib><creatorcontrib>McTigue, Michele A</creatorcontrib><creatorcontrib>Walcott, Makeba A</creatorcontrib><creatorcontrib>Nguyen-Phuong, Linh</creatorcontrib><creatorcontrib>Dionne, Kristin</creatorcontrib><creatorcontrib>Acker, Adam</creatorcontrib><creatorcontrib>Kiedrowski, Lesli A</creatorcontrib><creatorcontrib>Do, Andrew</creatorcontrib><creatorcontrib>Peterson, Jennifer L</creatorcontrib><creatorcontrib>Barth, Jaimie L</creatorcontrib><creatorcontrib>Yeap, Beow Y</creatorcontrib><creatorcontrib>Gainor, Justin F</creatorcontrib><creatorcontrib>Lin, Jessica J</creatorcontrib><creatorcontrib>Yoda, Satoshi</creatorcontrib><creatorcontrib>Hata, Aaron N</creatorcontrib><title>Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer</title><title>Nature cancer</title><addtitle>Nat Cancer</addtitle><description>Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.</description><subject>Aminopyridines</subject><subject>Anaplastic Lymphoma Kinase - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Humans</subject><subject>Lactams</subject><subject>Lactams, Macrocyclic - pharmacology</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles</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>eNpVkUtLxDAUhYMojuj8AReSpZtqXk2TjTCILxxwo-uQpukYaZOatAPu_OlmnFF0lUvuOd-9lwPAKUYXGFFxmRhFWBSIkAIhKmXB98AR4ZwUmLJq_089A_OU3hBCpMS4lOIQzGhZEY44PQKfC6-7j-QSDC3sQuz06Lyroc7fYZVgtGuruwQ1jEE3vR5gGyIcdVzZLFzBxq1tTBaa0A9h8k02ZNiovbGwn8ZMCz5B5-Fi-VgMIbkxG2A3ZavZiOIJOGjzADvfvcfg5fbm-fq-WD7dPVwvloVhiIyFoJIRXokKGy6bupRcUGpNbRrNTClIQyqqmUCMtaVB-XbOsZF1i1FLCGUNPQZXW-4w1b1tjPVj1J0aout1_FBBO_W_492rWoW1khUlQogMON8BYnifbBpV75KxXae9DVNSeTtJKJflRkq2UhNDStG2v2MwUpv01DY9ldNT3-kpnk1nfxf8tfxkRb8AAayYQw</recordid><startdate>20220601</startdate><enddate>20220601</enddate><creator>Shiba-Ishii, Aya</creator><creator>Johnson, Ted W</creator><creator>Dagogo-Jack, Ibiayi</creator><creator>Mino-Kenudson, Mari</creator><creator>Johnson, Theodore R</creator><creator>Wei, Ping</creator><creator>Weinrich, Scott L</creator><creator>McTigue, Michele A</creator><creator>Walcott, Makeba A</creator><creator>Nguyen-Phuong, Linh</creator><creator>Dionne, Kristin</creator><creator>Acker, Adam</creator><creator>Kiedrowski, Lesli A</creator><creator>Do, Andrew</creator><creator>Peterson, Jennifer L</creator><creator>Barth, Jaimie L</creator><creator>Yeap, Beow Y</creator><creator>Gainor, Justin F</creator><creator>Lin, Jessica J</creator><creator>Yoda, Satoshi</creator><creator>Hata, Aaron N</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8697-4081</orcidid><orcidid>https://orcid.org/0000-0003-4201-1392</orcidid><orcidid>https://orcid.org/0000-0001-5081-2005</orcidid><orcidid>https://orcid.org/0000-0002-9092-2265</orcidid><orcidid>https://orcid.org/0000-0001-7373-3916</orcidid><orcidid>https://orcid.org/0000-0002-6127-318X</orcidid></search><sort><creationdate>20220601</creationdate><title>Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer</title><author>Shiba-Ishii, Aya ; Johnson, Ted W ; Dagogo-Jack, Ibiayi ; Mino-Kenudson, Mari ; Johnson, Theodore R ; Wei, Ping ; Weinrich, Scott L ; McTigue, Michele A ; Walcott, Makeba A ; Nguyen-Phuong, Linh ; Dionne, Kristin ; Acker, Adam ; Kiedrowski, Lesli A ; Do, Andrew ; Peterson, Jennifer L ; Barth, Jaimie L ; Yeap, Beow Y ; Gainor, Justin F ; Lin, Jessica J ; Yoda, Satoshi ; Hata, Aaron N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-8394267871c69db596833ecbcda4c582d273a48044f5c0266661c9bf10f2234d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Aminopyridines</topic><topic>Anaplastic Lymphoma Kinase - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Humans</topic><topic>Lactams</topic><topic>Lactams, Macrocyclic - pharmacology</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shiba-Ishii, Aya</creatorcontrib><creatorcontrib>Johnson, Ted W</creatorcontrib><creatorcontrib>Dagogo-Jack, Ibiayi</creatorcontrib><creatorcontrib>Mino-Kenudson, Mari</creatorcontrib><creatorcontrib>Johnson, Theodore R</creatorcontrib><creatorcontrib>Wei, Ping</creatorcontrib><creatorcontrib>Weinrich, Scott L</creatorcontrib><creatorcontrib>McTigue, Michele A</creatorcontrib><creatorcontrib>Walcott, Makeba A</creatorcontrib><creatorcontrib>Nguyen-Phuong, Linh</creatorcontrib><creatorcontrib>Dionne, Kristin</creatorcontrib><creatorcontrib>Acker, Adam</creatorcontrib><creatorcontrib>Kiedrowski, Lesli A</creatorcontrib><creatorcontrib>Do, Andrew</creatorcontrib><creatorcontrib>Peterson, Jennifer L</creatorcontrib><creatorcontrib>Barth, Jaimie L</creatorcontrib><creatorcontrib>Yeap, Beow Y</creatorcontrib><creatorcontrib>Gainor, Justin F</creatorcontrib><creatorcontrib>Lin, Jessica J</creatorcontrib><creatorcontrib>Yoda, Satoshi</creatorcontrib><creatorcontrib>Hata, Aaron N</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>Nature cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shiba-Ishii, Aya</au><au>Johnson, Ted W</au><au>Dagogo-Jack, Ibiayi</au><au>Mino-Kenudson, Mari</au><au>Johnson, Theodore R</au><au>Wei, Ping</au><au>Weinrich, Scott L</au><au>McTigue, Michele A</au><au>Walcott, Makeba A</au><au>Nguyen-Phuong, Linh</au><au>Dionne, Kristin</au><au>Acker, Adam</au><au>Kiedrowski, Lesli A</au><au>Do, Andrew</au><au>Peterson, Jennifer L</au><au>Barth, Jaimie L</au><au>Yeap, Beow Y</au><au>Gainor, Justin F</au><au>Lin, Jessica J</au><au>Yoda, Satoshi</au><au>Hata, Aaron N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer</atitle><jtitle>Nature cancer</jtitle><addtitle>Nat Cancer</addtitle><date>2022-06-01</date><risdate>2022</risdate><volume>3</volume><issue>6</issue><spage>710</spage><epage>722</epage><pages>710-722</pages><issn>2662-1347</issn><eissn>2662-1347</eissn><abstract>Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. 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| subjects | Aminopyridines Anaplastic Lymphoma Kinase - genetics Carcinoma, Non-Small-Cell Lung - drug therapy Drug Resistance, Neoplasm - genetics Humans Lactams Lactams, Macrocyclic - pharmacology Lung Neoplasms - drug therapy Mutation Protein Kinase Inhibitors - pharmacology Pyrazoles |
| title | Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer |
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