FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor

Abstract

The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, and, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth and murine GIST tumor growth and maintenance The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response. We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. .

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

“…The magnitude of transcriptome change paralleled the effects on MAPK signaling inhibition, e.g., Figure 2A). ETV1 enhancer binding was far more divergent, consistent with the known observation that enhancer localization is lineage specific (19). We performed unsupervised k-means clustering of ETV1 enhancer peaks, which identified 3 clusters consisting of GIST-specific, melanoma-specific, and shared enhancer peaks ( Figure 2A).…”

“…We next performed ETV1 ChIP-sequencing (ChIP-seq) in GIST-T1, A375, and Colo800 cell lines and integrated the findings with prior ETV1 ChIP-seq profiles in GIST48 and GIST882 cells (15,19). We mapped global ETV1 peaks for each cell line, merged them, and annotated them as promoter (transcription MAPK signaling-dependent regulation of ETV1 protein stability, we performed a pooled genome-wide shRNA screen using a fluorescently tagged ETV1 as a high-throughput readout.…”

“…In GISTs, the ETS factor ETV1 is a lineage-specific master regulator that cooperates with KIT-and PDGFRA-activating mutations in pathogenesis (15)(16)(17)(18)(19). In cutaneous melanoma, ETV1 is recurrently amplified and cooperates with the BRAF V600E -activating mutation in oncogenesis (20,21).…”

A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor

“…MEK inhibitors contribute to antitumor activity in NF1 ‐mutant tumors by suppressing downstream ERK . MEK inhibition alone is ineffective in GIST because of MEK inhibitor‐induced feedback reactivation of upstream receptor tyrosine kinases, such as KIT or platelet‐derived growth factor receptor A (PDGFRA), in part through ETV1 . These mechanisms highlight the scientific rationale for using combination targeted treatment in GIST, including in KIT/PDGFRA wild‐type GIST.…”

“…). In addition to downregulation of ETV1, MEK inhibition targets the activated MAPK pathway, which results from NF1 loss . The other patient on this study with multiply refractory KIT ‐mutant GIST had a PFS of 6.1 months before demonstrating clinical progression.…”