10780432ccr171872-sup-185665_2_supp_4362643_rynqxt.xlsx (12.24 kB)
Table S2 from Targeting the MYCN–PARP–DNA Damage Response Pathway in Neuroendocrine Prostate Cancer
datasetposted on 2023-03-31, 19:48 authored by Wei Zhang, Bo Liu, Wenhui Wu, Likun Li, Bradley M. Broom, Spyridon P. Basourakos, Dimitrios Korentzelos, Yang Luan, Jianxiang Wang, Guang Yang, Sanghee Park, Abul Kalam Azad, Xuhong Cao, Jeri Kim, Paul G. Corn, Christopher J. Logothetis, Ana M. Aparicio, Arul M. Chinnaiyan, Nora Navone, Patricia Troncoso, Timothy C. Thompson
Differential expression result for Beltran's 70 classifier genes in PDX RNAseq dataset.
ARTICLE ABSTRACTPurpose: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC).Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN–PARP–DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN–PARP–DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivo.Conclusions: Our results identify a novel MYCN–PARP–DDR pathway that is driven by N-MYC in a subset of CRPC-Adeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC–regulated DDR gene targets and the biological and clinical significance of MYCN–PARP–DDR signaling will more fully elucidate the importance of the MYCN–PARP–DDR signaling pathway in the development and maintenance of NEPC. Clin Cancer Res; 24(3); 696–707. ©2017 AACR.
CarcinogenesisDNA damage and repairCell SignalingComputational MethodsGene expression profilingDrug MechanismsDrug-mediated stimulation of cell death pathwaysGene RegulationMechanisms of transcriptionGenitourinary CancersProstate cancerPharmacologyMolecular pharmacologyPreclinical ModelsXenograft modelsSmall Molecule Agents