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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b
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spelling	oai:doaj.org-article:c11b8d70dbc348e48996b9c35fbb436b2021-12-02T15:42:38ZFOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 03610.1038/s41523-021-00258-02374-4677https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00258-0https://doaj.org/toc/2374-4677Abstract 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.Steven P. AngusTimothy J. StuhlmillerGaurav MehtaSamantha M. BevillDaniel R. GouletJ. Felix Olivares-QuinteroMichael P. EastMaki TaniokaJon S. ZawistowskiDarshan SinghNoah SciakyXin ChenXiaping HeNaim U. RashidLynn Chollet-HintonCheng FanMatthew G. SolowayPatricia A. SpearsStuart JefferysJoel S. ParkerKristalyn K. GallagherAndres Forero-TorresIan E. KropAlastair M. ThompsonRashmi MurthyMichael L. GatzaCharles M. PerouH. Shelton EarpLisa A. CareyGary L. JohnsonNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
description	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.
format	article
author	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
author_facet	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
author_sort	Steven P. Angus
title	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
title_short	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
title_full	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
title_fullStr	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
title_full_unstemmed	FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
title_sort	foxa1 and adaptive response determinants to her2 targeted therapy in tbcrc 036
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c11b8d70dbc348e48996b9c35fbb436b
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FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

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