title: An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma.
abstract: Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma.
authors.affiliation: Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Salah-Eddine
authors.initials: SE
authors.lastname: Lamhamedi-Cherradi
authors.affiliation: Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Menegaz
authors.affiliation: Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vandhana
authors.initials: V
authors.lastname: Ramamoorthy
authors.affiliation: Shasta BioVentures, San Jose, California.
authors.forename: Ramani A
authors.initials: RA
authors.lastname: Aiyer
authors.affiliation: Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Maywald
authors.affiliation: Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adrianna S
authors.initials: AS
authors.lastname: Buford
authors.affiliation: Laboratory of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dannette K
authors.initials: DK
authors.lastname: Doolittle
authors.affiliation: Laboratory of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kirk S
authors.initials: KS
authors.lastname: Culotta
authors.affiliation: Star Biotechnology, LLC, San Francisco, California.
authors.forename: James E
authors.initials: JE
authors.lastname: O'Dorisio
authors.affiliation: Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas. jaludwig@mdanderson.org.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014018:Tissue Distribution; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C507942:Il2rg protein, mouse; D007211:Indoles; D053631:Interleukin Receptor Common gamma Subunit; C562345:YK 4-279