BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through Bim Induction

Abstract

Summary Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in Neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of chromatin regulator Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal new roles for BET bromodomains in MPNST development, and report a novel mechanism by which bromodomain inhibition induces apoptosis through induction of pro-apoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate novel epigenetic mechanisms underlying the balance of anti-/pro-apoptotic molecules, and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

“…Preclinical animal experiments showed that single use of BRD4 inhibitors exerted modest cytostatic effects, while the combination with a MEK inhibitor resulted in significant tumor regressions, with tumor shrinkages up to 67% of mice [20]. This observation was confirmed by a previous study from Patel et al [52], who also reported that BRD4 inhibition in MPNSTs profoundly suppressed both growth and tumorigenesis. Additional exciting preclinical results were seen with inhibition of Aurora kinase A using selective inhibitor MLN8237, which stabilized tumor volume and significantly increased survival of mice with MPNST xenografts [53].…”

BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway

“…Previous studies have demonstrated that BRD4 promotes cell cycle progression and regulates cell growth and transcription (13). Subsequent studies have demonstrated that BRD4 serves a critical role in tumor proliferation and growth in melanoma (14), neuroblastoma (15), glioblastoma (16), malignant peripheral nerve sheath tumors (17), lymphoblastic leukemia (18) and lung adenocarcinoma (19). However, to the best of our knowledge, the involvement of BRD4 in migration and invasion has not been reported in HCC.…”

“…BRD4 has been demonstrated to serve a critical role in carcinogenesis and progression of various types of human cancer (14,16,17). However, the role of BRD4 in cancer metastasis has not been illustrated.…”

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

“…Fine scissors was used to cut and separate the nerve roots and DRGs. DRG and/or nerve root neurosphere culture was performed as previously described (Le et al, 2009; Patel et al, 2014; Ratner et al, 2006). For cell proliferation assay, the single sphere cells were seeded to 6 well plate coated with poly-D-lysine/laminin (4.0×10 3 cells per well) for monolayer culture.…”