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

Autor: Angus SP; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA., Stuhlmiller TJ; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., Mehta G; Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Bevill SM; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA.; Massachusetts General Hospital, Cambridge, MA, USA., Goulet DR; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA.; Koch Institute, Massachusetts Institute of Technology, Boston, MA, USA., Olivares-Quintero JF; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., East MP; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., Tanioka M; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Hyogo Cancer Center, Akashi, Japan., Zawistowski JS; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., Singh D; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., Sciaky N; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., Chen X; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA., He X; Department of Genetics, UNC Chapel Hill, Chapel Hill, NC, USA., Rashid NU; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Biostatistics, UNC Chapel Hill, Chapel Hill, NC, USA., Chollet-Hinton L; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA., Fan C; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA., Soloway MG; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA., Spears PA; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA., Jefferys S; Department of Genetics, UNC Chapel Hill, Chapel Hill, NC, USA., Parker JS; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Genetics, UNC Chapel Hill, Chapel Hill, NC, USA., Gallagher KK; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Surgery, UNC Chapel Hill, Chapel Hill, NC, USA., Forero-Torres A; University of Alabama-Birmingham School of Medicine, Birmingham, AL, USA.; Seattle Genetics, Inc., Seattle, WA, USA., Krop IE; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Thompson AM; Department of Breast Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA.; Baylor College of Medicine, Houston, TX, USA., Murthy R; Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA., Gatza ML; Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Perou CM; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Genetics, UNC Chapel Hill, Chapel Hill, NC, USA., Earp HS; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA.; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA., Carey LA; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA., Johnson GL; Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA. glj@med.unc.edu.; UNC Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA. glj@med.unc.edu.
Jazyk: angličtina
Zdroj: NPJ breast cancer [NPJ Breast Cancer] 2021 May 12; Vol. 7 (1), pp. 51. Date of Electronic Publication: 2021 May 12.
DOI: 10.1038/s41523-021-00258-0
Abstrakt: 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.
Databáze: MEDLINE