Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons.

There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where ZBTB16/RARA rearrangements are critical disease drivers.

An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients.

BACKGROUND: NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. METHODS: Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). RESULTS: For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. CONCLUSIONS: We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.

"Z4" Complex Member Fusions in NUT Carcinoma: Implications for a Novel Oncogenic Mechanism.

Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of NUT-fusion oncogenes resulting from chromosomal translocation. In most cases, the NUT gene (NUTM1) is fused to bromodomain containing 4 (BRD4) forming the BRD4-NUT oncogene. Here, a novel fusion partner to NUT was discovered using next-generation sequencing and FISH from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex. In BRD4-NUT-expressing NC cells, wild-type ZNF592 and other associated "Z4" complex proteins, including ZNF532 and ZMYND8, colocalize with BRD4-NUT in characteristic nuclear foci. Furthermore, ectopic expression of BRD4-NUT in a non-NC cell line induces sequestration of Z4 factors to BRD4-NUT foci. Finally, the data demonstrate the specific dependency of NC cells on Z4 modules, ZNF532 and ZNF592. IMPLICATIONS: This study establishes the oncogenic role of Z4 factors in NC, offering potential new targeted therapeutic strategies in this incurable cancer.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.