SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors

Abstract

The antitumor activity of bromodomain and extraterminal motif protein inhibitors (BETi) has been demonstrated across numerous types of cancer. As such, these inhibitors are currently undergoing widespread clinical evaluation. However, predictive biomarkers allowing the stratification of tumors into responders and nonresponders to BETi are lacking. Here, we showed significant antiproliferative effects of low dosage BETi in vitro and in vivo against aggressive ovarian and lung cancer models lacking SMARCA4 and SMARCA2, key components of SWI/SNF chromatin remodeling complexes. Restoration of SMARCA4 or SMARCA2 promoted resistance to BETi in these models and, conversely, knockdown of SMARCA4 sensitized resistant cells to BETi. Transcriptomic analysis revealed that exposure to BETi potently downregulated a network of genes involved in receptor tyrosine kinase (RTK) signaling in SMARCA4/A2deficient cells, including the oncogenic RTK HER3. Repression of signaling downstream of HER3 was found to be an important determinant of response to BETi in SMARCA4/ A2-deficient cells. Overall, we propose that BETi represent a rational therapeutic strategy in poor-prognosis, SMARCA4/ A2-deficient cancers.

Small-Cell Carcinoma of the Ovary, Hypercalcemic Type–Genetics, New Treatment Targets, and Current Management Guidelines

“…In addition to targeting EZH2 and HDAC, bromodomain and extra-terminal motif containing protein inhibitors (BETi) have been explored in SCCOHT models, based on previous studies showing the dependency of SMARCA4-mutant esophageal cancer models for BET protein BRD4 (59) and the coregulation of an oncogenic network by BRD4 and SMARCA4 in acute leukemia (60). Consistent with these findings, SCCOHT cells were highly sensitive to BETi JQ1 and OTX015, the latter of which showed strong anti-tumor activities in an orthotopic xenograft model of SCCOHT (61). In addition to BRD4, other BET proteins have been linked to SWI/SNF function.…”

Exome sequencing identifies ARID2 as a novel tumor suppressor in early-onset sporadic rectal cancer

“…In addition to its well documented role in regulating gene expression 50, 51 , ARID2 plays a dual role in DNA repair by a) interacting with RAD1 to promote homology directed repair 11 and b) promoting transcriptional repression in double strand break repair 37 . Considering the recent interest to develop targeted therapy against SWI/SNF deficient cancers 44 , it is interesting to determine whether the tumor suppressor role of ARID2 in CRC is dependent on its transcription regulatory or DNA repair function(s). Given the recalcitrance of advanced colorectal tumors to conventional therapies and the identification of PBAF inactivation association with increased susceptibility to killing by cytotoxic T cells 41 , our identification of ARID2 loss in a significant proportion of EOSRC, a poorly studied CRC subtype, assumes significance.…”

Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

“…One can perhaps envisage a ‘dosage’ effect due to partial ARID1B cytoplasmic localization as well. Given the recent identification of SWI/SNF deficient tumors being susceptible to Bromodomain inhibitors acting through suppression of RAS-ERK signaling 28 and the recent demonstration of effective pancreatic tumor regression in genetically engineered mice as well as in patient derived mouse xenografts when subjected to combined EGFR/c-RAF ablation 3 , the novel RAF-ERK activating function of cytoplasm-localized ARID1B can be explored for therapeutic options.…”