Browsing by Author "Gatza, Michael L."

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    FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036
    (Springer Nature, 2021-05-12) Angus, Steven P.; Stuhlmiller, Timothy J.; Mehta, Gaurav; Bevill, Samantha M.; Goulet, Daniel R.; Olivares-Quintero, J. Felix; East, Michael P.; Tanioka, Maki; Zawistowski, Jon S.; Singh, Darshan; Sciaky, Noah; Chen, Xin; He, Xiaping; Rashid, Naim U.; Chollet-Hinton, Lynn; Fan, Cheng; Soloway, Matthew G.; Spears, Patricia A.; Jefferys, Stuart; Parker, Joel S.; Gallagher, Kristalyn K.; Forero-Torres, Andres; Krop, Ian E.; Thompson, Alastair M.; Murthy, Rashmi; Gatza, Michael L.; Perou, Charles M.; Earp, H. Shelton; Carey, Lisa A.; Johnson, Gary L.; Pediatrics, School of Medicine
    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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    SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
    (Springer Nature, 2021-04-09) Mehta, Gaurav A.; Angus, Steven P.; Khella, Christen A.; Tong, Kevin; Khanna, Pooja; Dixon, Shelley A.H.; Verzi, Michael P.; Johnson, Gary L.; Gatza, Michael L.; Pediatrics, School of Medicine
    Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.