TY - JOUR
T1 - FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
AU - Angus, Steven P.
AU - Stuhlmiller, Timothy J.
AU - Mehta, Gaurav
AU - Bevill, Samantha M.
AU - Goulet, Daniel R.
AU - Olivares-Quintero, J. Felix
AU - East, Michael P.
AU - Tanioka, Maki
AU - Zawistowski, Jon S.
AU - Singh, Darshan
AU - Sciaky, Noah
AU - Chen, Xin
AU - He, Xiaping
AU - Rashid, Naim U.
AU - Chollet-Hinton, Lynn
AU - Fan, Cheng
AU - Soloway, Matthew G.
AU - Spears, Patricia A.
AU - Jefferys, Stuart
AU - Parker, Joel S.
AU - Gallagher, Kristalyn K.
AU - Forero-Torres, Andres
AU - Krop, Ian E.
AU - Thompson, Alastair M.
AU - Murthy, Rashmi
AU - Gatza, Michael L.
AU - Perou, Charles M.
AU - Earp, H. Shelton
AU - Carey, Lisa A.
AU - Johnson, Gary L.
N1 - Funding Information:
We thank GlaxoSmithKline, Genentech/Roche, and the Translational Breast Cancer Research Consortium. GlaxoSmithKline provided lapatinib and Genentech/Roche provided trastuzumab and pertuzumab free of charge. We also thank the patients and their family members for participation in the LCCC1214/TBCRC 036 trial. This clinical research (ClinicalTrials.gov Identifier: NCT01875666) was funded by the Susan G. Komen Foundation IIR12-225201 (G.L.J., H.S.E., and L.A.C.), UNC Breast SPORE CA058223 (H.S.E., C.M.P., L.A.C., and G.L.J.), NIH grants U01CA238475 (C.M.P. and G.L.J.) and U24DK116204 (G.L.J.), UNC Junior Faculty Development Award (S.P.A.), Translational Breast Cancer Research Consortium (L.A.C.), and the UNC University Cancer Research Fund.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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U2 - 10.1038/s41523-021-00258-0
DO - 10.1038/s41523-021-00258-0
M3 - Article
AN - SCOPUS:85105786682
SN - 2374-4677
VL - 7
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 51
ER -
