title: 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 MYC-driven 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 MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. ©2016 AACR.
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Sun
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Mylissa A
authors.initials: MA
authors.lastname: Borek
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Dellarocca
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Maria Elena S
authors.initials: ME
authors.lastname: Samson
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Anna W
authors.initials: AW
authors.lastname: Ma
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Guang-Xin
authors.initials: GX
authors.lastname: Xu
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Troy
authors.initials: T
authors.lastname: Patterson
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: Tuck
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Jaye L
authors.initials: JL
authors.lastname: Viner
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Fattaey
authors.affiliation: Curis, Inc., Lexington, Massachusetts. jwang2@tesarobio.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D059748:Proteolysis; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors