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 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.

Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation

“…We then test whether GBP family gene region is relocated into LLPS zone in the process of immune activation. Based on previous BRD4 and MED1 ChIP-seq data 45 , we found that GBP family genome regions were enriched with these two phase separation marker proteins (Fig. 4d ).…”

FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

“…These results underscore the requirement for FOXA1 in lapatinib-resistant, HER2+ disease. Patient data support this conclusion where breast tumors with decreased expression of FOXA1 were less proliferative, had reduced ERBB2/ERBB3 (HER2/HER3) expression, and increased enrichment of immune signatures [167]. As a whole, these studies revealed that the function of FOXA1 extends beyond its canonical role of modulating ER activity in breast cancer.…”

“…Mechanisms of acquired lapatinib (EGFR/HER2 inhibitor) resistance are diverse, including expression of truncated/activated HER2 and elevated PI3K/AKT signaling that lead to dramatic epigenetic and transcriptional changes. Angus et al found that a large number of superenhancers are acquired in the context of lapatinib resistance, including those at the ERBB2 (HER2), PBX1, and FOXA1 genes [167]. They further revealed that the increased expression of FOXA1 is essential for proliferation of lapatinib-resistant cell lines and, in a feed-forward manner, induced the expression of ERBB3 (HER3).…”

“…Third, NR crosstalk can reprogram FOXA1 chromatin binding, which can also contribute to therapy resistance and compensatory pathway activation [58,[148][149][150]154,156,158,168,169]. Increased FOXA1 expression can also suppress the tumor immune response, which is associated with worse patient outcomes [162,167,170]. Lastly, genetic approaches inhibiting FOXA1 expression within the contexts mentioned above result in decreased tumor cell proliferation, reversal of therapy resistance, and increased the tumor immune response.…”

FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer

“…Experimental overexpression of HER2 in mammary epithelial cells in MMTV-Neu transgenic mice is sufficient to produce breast cancers in vivo demonstrating its transforming ability (10, 11). Interestingly, despite low levels of ERα expression, FOXA1 is expressed in many HER2- positive tumors, where its expression correlates with higher rates of cell proliferation (12). It has been proposed that there is cross-regulation between HER2 and FOXA1 in ERα-negative breast tumors involving several other transcription factors, including RELB, PAK1, and TLE3 (13).…”