FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP activ...
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Autor*in:	Steven P. Angus [verfasserIn] Timothy J. Stuhlmiller [verfasserIn] Gaurav Mehta [verfasserIn] Samantha M. Bevill [verfasserIn] Daniel R. Goulet [verfasserIn] J. Felix Olivares-Quintero [verfasserIn] Michael P. East [verfasserIn] Maki Tanioka [verfasserIn] Jon S. Zawistowski [verfasserIn] Darshan Singh [verfasserIn] Noah Sciaky [verfasserIn] Xin Chen [verfasserIn] Xiaping He [verfasserIn] Naim U. Rashid [verfasserIn] Lynn Chollet-Hinton [verfasserIn] Cheng Fan [verfasserIn] Matthew G. Soloway [verfasserIn] Patricia A. Spears [verfasserIn] Stuart Jefferys [verfasserIn] Joel S. Parker [verfasserIn] Kristalyn K. Gallagher [verfasserIn] Andres Forero-Torres [verfasserIn] Ian E. Krop [verfasserIn] Alastair M. Thompson [verfasserIn] Rashmi Murthy [verfasserIn] Michael L. Gatza [verfasserIn] Charles M. Perou [verfasserIn] H. Shelton Earp [verfasserIn] Lisa A. Carey [verfasserIn] Gary L. Johnson [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Übergeordnetes Werk:	In: npj Breast Cancer - Nature Portfolio, 2016, 7(2021), 1, Seite 15
Übergeordnetes Werk:	volume:7 ; year:2021 ; number:1 ; pages:15

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41523-021-00258-0

Katalog-ID:	DOAJ06835505X

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allfields	10.1038/s41523-021-00258-0 doi (DE-627)DOAJ06835505X (DE-599)DOAJc11b8d70dbc348e48996b9c35fbb436b DE-627 ger DE-627 rakwb eng RC254-282 Steven P. Angus verfasserin aut FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Timothy J. Stuhlmiller verfasserin aut Gaurav Mehta verfasserin aut Samantha M. Bevill verfasserin aut Daniel R. Goulet verfasserin aut J. Felix Olivares-Quintero verfasserin aut Michael P. East verfasserin aut Maki Tanioka verfasserin aut Jon S. Zawistowski verfasserin aut Darshan Singh verfasserin aut Noah Sciaky verfasserin aut Xin Chen verfasserin aut Xiaping He verfasserin aut Naim U. Rashid verfasserin aut Lynn Chollet-Hinton verfasserin aut Cheng Fan verfasserin aut Matthew G. Soloway verfasserin aut Patricia A. Spears verfasserin aut Stuart Jefferys verfasserin aut Joel S. Parker verfasserin aut Kristalyn K. Gallagher verfasserin aut Andres Forero-Torres verfasserin aut Ian E. Krop verfasserin aut Alastair M. Thompson verfasserin aut Rashmi Murthy verfasserin aut Michael L. Gatza verfasserin aut Charles M. Perou verfasserin aut H. Shelton Earp verfasserin aut Lisa A. Carey verfasserin aut Gary L. Johnson verfasserin aut In npj Breast Cancer Nature Portfolio, 2016 7(2021), 1, Seite 15 (DE-627)844762113 (DE-600)2843288-5 23744677 nnns volume:7 year:2021 number:1 pages:15 https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b kostenfrei https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/toc/2374-4677 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2021 1 15
spelling	10.1038/s41523-021-00258-0 doi (DE-627)DOAJ06835505X (DE-599)DOAJc11b8d70dbc348e48996b9c35fbb436b DE-627 ger DE-627 rakwb eng RC254-282 Steven P. Angus verfasserin aut FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Timothy J. Stuhlmiller verfasserin aut Gaurav Mehta verfasserin aut Samantha M. Bevill verfasserin aut Daniel R. Goulet verfasserin aut J. Felix Olivares-Quintero verfasserin aut Michael P. East verfasserin aut Maki Tanioka verfasserin aut Jon S. Zawistowski verfasserin aut Darshan Singh verfasserin aut Noah Sciaky verfasserin aut Xin Chen verfasserin aut Xiaping He verfasserin aut Naim U. Rashid verfasserin aut Lynn Chollet-Hinton verfasserin aut Cheng Fan verfasserin aut Matthew G. Soloway verfasserin aut Patricia A. Spears verfasserin aut Stuart Jefferys verfasserin aut Joel S. Parker verfasserin aut Kristalyn K. Gallagher verfasserin aut Andres Forero-Torres verfasserin aut Ian E. Krop verfasserin aut Alastair M. Thompson verfasserin aut Rashmi Murthy verfasserin aut Michael L. Gatza verfasserin aut Charles M. Perou verfasserin aut H. Shelton Earp verfasserin aut Lisa A. Carey verfasserin aut Gary L. Johnson verfasserin aut In npj Breast Cancer Nature Portfolio, 2016 7(2021), 1, Seite 15 (DE-627)844762113 (DE-600)2843288-5 23744677 nnns volume:7 year:2021 number:1 pages:15 https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b kostenfrei https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/toc/2374-4677 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2021 1 15
allfields_unstemmed	10.1038/s41523-021-00258-0 doi (DE-627)DOAJ06835505X (DE-599)DOAJc11b8d70dbc348e48996b9c35fbb436b DE-627 ger DE-627 rakwb eng RC254-282 Steven P. Angus verfasserin aut FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Timothy J. Stuhlmiller verfasserin aut Gaurav Mehta verfasserin aut Samantha M. Bevill verfasserin aut Daniel R. Goulet verfasserin aut J. Felix Olivares-Quintero verfasserin aut Michael P. East verfasserin aut Maki Tanioka verfasserin aut Jon S. Zawistowski verfasserin aut Darshan Singh verfasserin aut Noah Sciaky verfasserin aut Xin Chen verfasserin aut Xiaping He verfasserin aut Naim U. Rashid verfasserin aut Lynn Chollet-Hinton verfasserin aut Cheng Fan verfasserin aut Matthew G. Soloway verfasserin aut Patricia A. Spears verfasserin aut Stuart Jefferys verfasserin aut Joel S. Parker verfasserin aut Kristalyn K. Gallagher verfasserin aut Andres Forero-Torres verfasserin aut Ian E. Krop verfasserin aut Alastair M. Thompson verfasserin aut Rashmi Murthy verfasserin aut Michael L. Gatza verfasserin aut Charles M. Perou verfasserin aut H. Shelton Earp verfasserin aut Lisa A. Carey verfasserin aut Gary L. Johnson verfasserin aut In npj Breast Cancer Nature Portfolio, 2016 7(2021), 1, Seite 15 (DE-627)844762113 (DE-600)2843288-5 23744677 nnns volume:7 year:2021 number:1 pages:15 https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b kostenfrei https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/toc/2374-4677 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2021 1 15
allfieldsGer	10.1038/s41523-021-00258-0 doi (DE-627)DOAJ06835505X (DE-599)DOAJc11b8d70dbc348e48996b9c35fbb436b DE-627 ger DE-627 rakwb eng RC254-282 Steven P. Angus verfasserin aut FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Timothy J. Stuhlmiller verfasserin aut Gaurav Mehta verfasserin aut Samantha M. Bevill verfasserin aut Daniel R. Goulet verfasserin aut J. Felix Olivares-Quintero verfasserin aut Michael P. East verfasserin aut Maki Tanioka verfasserin aut Jon S. Zawistowski verfasserin aut Darshan Singh verfasserin aut Noah Sciaky verfasserin aut Xin Chen verfasserin aut Xiaping He verfasserin aut Naim U. Rashid verfasserin aut Lynn Chollet-Hinton verfasserin aut Cheng Fan verfasserin aut Matthew G. Soloway verfasserin aut Patricia A. Spears verfasserin aut Stuart Jefferys verfasserin aut Joel S. Parker verfasserin aut Kristalyn K. Gallagher verfasserin aut Andres Forero-Torres verfasserin aut Ian E. Krop verfasserin aut Alastair M. Thompson verfasserin aut Rashmi Murthy verfasserin aut Michael L. Gatza verfasserin aut Charles M. Perou verfasserin aut H. Shelton Earp verfasserin aut Lisa A. Carey verfasserin aut Gary L. Johnson verfasserin aut In npj Breast Cancer Nature Portfolio, 2016 7(2021), 1, Seite 15 (DE-627)844762113 (DE-600)2843288-5 23744677 nnns volume:7 year:2021 number:1 pages:15 https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b kostenfrei https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/toc/2374-4677 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2021 1 15
allfieldsSound	10.1038/s41523-021-00258-0 doi (DE-627)DOAJ06835505X (DE-599)DOAJc11b8d70dbc348e48996b9c35fbb436b DE-627 ger DE-627 rakwb eng RC254-282 Steven P. Angus verfasserin aut FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Timothy J. Stuhlmiller verfasserin aut Gaurav Mehta verfasserin aut Samantha M. Bevill verfasserin aut Daniel R. Goulet verfasserin aut J. Felix Olivares-Quintero verfasserin aut Michael P. East verfasserin aut Maki Tanioka verfasserin aut Jon S. Zawistowski verfasserin aut Darshan Singh verfasserin aut Noah Sciaky verfasserin aut Xin Chen verfasserin aut Xiaping He verfasserin aut Naim U. Rashid verfasserin aut Lynn Chollet-Hinton verfasserin aut Cheng Fan verfasserin aut Matthew G. Soloway verfasserin aut Patricia A. Spears verfasserin aut Stuart Jefferys verfasserin aut Joel S. Parker verfasserin aut Kristalyn K. Gallagher verfasserin aut Andres Forero-Torres verfasserin aut Ian E. Krop verfasserin aut Alastair M. Thompson verfasserin aut Rashmi Murthy verfasserin aut Michael L. Gatza verfasserin aut Charles M. Perou verfasserin aut H. Shelton Earp verfasserin aut Lisa A. Carey verfasserin aut Gary L. Johnson verfasserin aut In npj Breast Cancer Nature Portfolio, 2016 7(2021), 1, Seite 15 (DE-627)844762113 (DE-600)2843288-5 23744677 nnns volume:7 year:2021 number:1 pages:15 https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b kostenfrei https://doi.org/10.1038/s41523-021-00258-0 kostenfrei https://doaj.org/toc/2374-4677 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2021 1 15
language	English
source	In npj Breast Cancer 7(2021), 1, Seite 15 volume:7 year:2021 number:1 pages:15
sourceStr	In npj Breast Cancer 7(2021), 1, Seite 15 volume:7 year:2021 number:1 pages:15
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	npj Breast Cancer
authorswithroles_txt_mv	Steven P. Angus @@aut@@ Timothy J. Stuhlmiller @@aut@@ Gaurav Mehta @@aut@@ Samantha M. Bevill @@aut@@ Daniel R. Goulet @@aut@@ J. Felix Olivares-Quintero @@aut@@ Michael P. East @@aut@@ Maki Tanioka @@aut@@ Jon S. Zawistowski @@aut@@ Darshan Singh @@aut@@ Noah Sciaky @@aut@@ Xin Chen @@aut@@ Xiaping He @@aut@@ Naim U. Rashid @@aut@@ Lynn Chollet-Hinton @@aut@@ Cheng Fan @@aut@@ Matthew G. Soloway @@aut@@ Patricia A. Spears @@aut@@ Stuart Jefferys @@aut@@ Joel S. Parker @@aut@@ Kristalyn K. Gallagher @@aut@@ Andres Forero-Torres @@aut@@ Ian E. Krop @@aut@@ Alastair M. Thompson @@aut@@ Rashmi Murthy @@aut@@ Michael L. Gatza @@aut@@ Charles M. Perou @@aut@@ H. Shelton Earp @@aut@@ Lisa A. Carey @@aut@@ Gary L. Johnson @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	844762113
id	DOAJ06835505X
language_de	englisch
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callnumber-first	R - Medicine
author	Steven P. Angus
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topic_title	RC254-282 FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
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title	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
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author_browse	Steven P. Angus Timothy J. Stuhlmiller Gaurav Mehta Samantha M. Bevill Daniel R. Goulet J. Felix Olivares-Quintero Michael P. East Maki Tanioka Jon S. Zawistowski Darshan Singh Noah Sciaky Xin Chen Xiaping He Naim U. Rashid Lynn Chollet-Hinton Cheng Fan Matthew G. Soloway Patricia A. Spears Stuart Jefferys Joel S. Parker Kristalyn K. Gallagher Andres Forero-Torres Ian E. Krop Alastair M. Thompson Rashmi Murthy Michael L. Gatza Charles M. Perou H. Shelton Earp Lisa A. Carey Gary L. Johnson
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title_sort	foxa1 and adaptive response determinants to her2 targeted therapy in tbcrc 036
callnumber	RC254-282
title_auth	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
abstract	Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
abstractGer	Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
abstract_unstemmed	Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
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title_short	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
url	https://doi.org/10.1038/s41523-021-00258-0 https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b https://doaj.org/toc/2374-4677
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