Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Abstract

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

“…As expected from our previous findings (Dominguez-Sola et al, 2012), Gene Set Enrichment Analysis (GSEA) (Subramanian et al, 2005) revealed strong upregulation of gene signatures associated with the cellular response to c-Myc (Schuhmacher et al, 2001; Sun et al, 2017; Zeller et al, 2003) (Fig. S1A).…”

Comprehensive evaluation of context dependence of the prognostic impact of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project

“…Moving forward, as newer agents intended to target Myc family proteins are developed, our results suggest potential subgroups of particular interest for these approaches. Examples of potential strategies to target MYCN and downstream dependencies include bromodomain inhibition, dual HDAC/PI3K inhibition, MDM2 inhibition, and aurora A kinase inhibition . Whether patients with MYCN‐A as their sole unfavorable prognostic factor will be more likely to benefit from these strategies will require further study.…”

NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment

“…Currently, a phase I trial investigating a dual HDACi/PI3K inhibitor, CUDC‐907 is open to enrolling NC patients (NCT02307240). Activity of this drug in NC cells has been demonstrated in vitro and in vivo, and is associated with rapidly decreased MYC levels, a key oncogenic target of BRD4‐NUT . As with BETi, it is likely that effective therapy will require a combinatorial approach.…”