In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

Abstract

Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1-4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.

Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer

“…On the other hand, genetic mutations of the core subunits are rarely found in human cancers. Instead, the DPY30 (51), ASH2L (24,52), and WDR5 (25,53,54) core subunits have been found to be overexpressed in cancers, show correlation of high expression levels with poor prognosis, and, in some cases, functionally promote tumorigenesis. Such differential regulations and roles elicit interesting questions relating to the exact roles of these subunits and the associated H3K4 methylation in cancer and merit further investigation.…”

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

“…Recent reports indicate that WDR5 is needed for proliferation and DNA replication. Two available WDR5 inhibitors with low efficacy, OICR-9429 and MM-401, show that WDR5 inhibition slowed proliferation in pancreatic cancer [190]. OICR-9429 antagonizes the WDR5–MLL interaction, selectively inhibited proliferation, and induced differentiation in human AML cells [191]; in contrast, MM-401 targets the MLL1 H3K4 methyltransferase activity and was able to inhibit MLL1 activity by blocking MLL1–WDR5 interaction and complex assembly, specifically blocking proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells [192].…”

Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma

“…Aberrant overexpression of WDR5 has been found in multiple human malignancies such as bladder, pancreatic, breast cancer, and leukemia. Its overexpression usually correlated with cancer aggressiveness and unfavorable prognosis in these cancers . Moreover, interactions between WDR5 and MYC, HDAC3 or histone H3 threonine 11 phosphorylation (H3T11P) are essential for hypoxia‐induced EMT, MYC‐driven carcinogenesis as well as androgen‐dependent cell proliferation, respectively .…”