Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

Abstract

Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds. Combination of both compounds efficiently represses antiapoptotic genes and the oncogene MYC. Our results provide a novel approach for the treatment of RT.

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

“…Immunoblots of lysates from the spleens of MLL-2-engrafted mice showed that all treatments resulted in depletion of MYC and BCL2 (supplemental Figure 3) as in previous reports. 18 Consistent with on-target activity of CDKI-73, we observed reduced RNAPII-Ser2 phosphorylation with the single treatment (29%), which was further reduced (49%) in the combination. Most strikingly, combination treatment resulted in further reduction of the antiapoptotic protein MCL1, and increased levels of cleaved caspase 3, compared with either single agent alone, consistent with increased cell killing.…”

Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

“…These data suggest that BET inhibition by JQ1 can suppress MYC expression and activity in ATRT cells and significantly restrict cell growth, consistent with a recent report by Moreno et al who demonstrated a synergy between BRD4 and CDK9 inhibition in ATRT cells. 22 Interestingly, our data on BT16 cell responsiveness diverge from that of Trochia et al who showed relative resistance of BT 16 to JQ1 by MTS assay. 7 These differences could be due to measuring of long term growth compared to the short-term assay performed by Torchia et al 7 To determine whether the anti-tumorigenic capacity of BET-mediated MYC inhibition is extended to primary human tumors, we obtained cells from an ATRT patient biopsy and tested the impact of JQ1 in a short-term culture (MAF-794).…”

“…These data suggest that BET inhibition by JQ1 can suppress MYC expression and activity in ATRT cells and significantly restrict cell growth, consistent with a recent report by Moreno et al . who demonstrated a synergy between BRD4 and CDK9 inhibition in ATRT cells . Interestingly, our data on BT16 cell responsiveness diverge from that of Trochia et al who showed relative resistance of BT 16 to JQ1 by MTS assay .…”

“…also reported sensitivity of Group1 tumors to JQ1 indicating broad applicability of BET inhibition in ATRT . In corroboration, a recent report demonstrates that combining the use of BET inhibition and inhibiting CDK9 can lead to effective suppression of ATRT cell growth, a finding that fortifies our notion that MYC inhibition is a promising new strategy for targeting SMARCB1‐deleted tumors. Multiple BET protein inhibitors are now in clinical trials.…”

Therapeutic targeting of transcriptional cyclin-dependent kinases

“…Rational combination therapies are likely to greatly extend the therapeutic applications of selective inhibitors of tCDKs. Mechanistic studies and synthetic lethality screens have already numerous revealed pathways, other targeted agents, or conventional chemotherapeutics that can synergize with tCDK inhibitors [58,116,140,[144][145][146][147], and additional examples are likely to exist.…”