Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

Abstract

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.bromodomain inhibitor | TRIM33 | JQ1 | drug resistance | TGF-β

Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

“…We showed that GS-626510, a novel oral BET inhibitor, has remarkable activity against chemotherapy-resistant cell lines not only in vitro but also in vivo against xenografts and PDXs established from patients harboring chemotherapy-resistant tumors. These preclinical data with JQ1 and GS-626510 in primary ovarian cancer cell lines and xenografts confirm and expand the results of recent in-tumor shRNA genetic screens revealing c-MYC overexpression as a therapeutic target in chemotherapy-resistant tumors through the use of BRD4 inhibitors (27,28). While previous studies have found that some ovarian tumors may contain BRD4 amplifications and that such tumors may respond to BET inhibition (29), the prevalence of these amplifications in ovarian cancer tends to be low (30).…”

Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

“…Recently, more potent and specific TBK1 (compound 1) and BET (GS-626510) inhibitors have been described (Jenkins et al, 2018; Shi et al, 2016). We therefore utilized an aggressive KL patient-derived xenograft (PDX) model (DFCI-366) to design a combination therapy schedule for potential future translation to the clinic.…”

“…Finally, we also used recently described potent and selective TBK1 and BET inhibitors (Jenkins et al, 2018; Shi et al, 2016) as tool compounds to develop a therapeutic strategy with translatable potential for KRAS-driven NSCLC patients. The alternating doublet strategy minimizes the toxicity of inhibiting each target, limits DDI, and also provides a faster path to the clinic compared with triple combination therapies that require complex dose escalation schedules.…”

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

“…2E; refs. 19,43,44), as well as hyperphosphorylation and increased stability due to the inactivation of native E3 ligases such as SPOP or TRIM33 (37,45,46). Many of these mechanisms can be prevented through the use of a BET degrader.…”