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The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Chemical Proteomics Cal51

ABSTRACT: PARP1 inhibitors (PARP1is) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determined the differential efficacy of multiple clinical PARP1is in SCLC cells. Compared to the other PARP1is (rucaparib, olaparib and niraparib), talazoparib displayed the highest potency across SCLC, also in SLFN11-negative cells. Chemical proteomics identified PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduced cell survival, particularly in combination with PARP1 inhibition. Drug combination screening revealed talazoparib synergy with the WEE1/PLK1 inhibitor, adavosertib. Global phosphoproteomics identified disparate effects on cell cycle and DNA damage response signaling, illustrating underlying mechanisms. Synergy with adavosertib was more pronounced for talazoparib than olaparib and silencing PARP16 further reduced cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib’s overall mechanism of action and constitutes a new actionable target in SCLC.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Epithelium

DISEASE(S): Breast Cancinoma

SUBMITTER: John Koomen

LAB HEAD: Uwe Rix, PhD

PROVIDER: PXD020520 | Pride | 2021-07-21

REPOSITORIES: Pride

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			Action	DRS
	20141205_CKRix_PD389.RAW	Raw
	20141205_CKRix_PD389.RAWF008716.mzid.gz	Mzid
	20141205_CKRix_PD389.RAWF008716.mzid_20141205_CKRix_PD389.RAW_F008716.MGF	Mzid
	20141205_CKRix_PD389.RAW_F008716.dta	Raw
	20141205_CKRix_PD390.RAW	Raw

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Project description:MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MBs to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. We here characterize the transcriptional effects of class I HDAC inhibition in MYC-driven MB and explore beneficial drug combinations. MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile compared to untreated control were quantified on a microarray. Gene set enrichment analysis, cytoscape enrichment mapping and ingenuity pathway analysis led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested as single agents in metabolic activity assays in three MYC-amplified and two non-MYC-amplified MB cell lines. Synergy with entinostat was evaluated by dose response curve shift, combination index and zero interaction potency synergy model and validated in cell count and flow cytometry experiments in two MYC-amplified and one non-MYC-amplified MB cell line. The effect of the most promising drug combination (entinostat and olaparib) on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat. The combination of entinostat and olaparib led to increased cell death, decreased viability and increased formation of double strand breaks selectively in MYC-amplified MB cells. MYC-amplified MB cells treated with entinostat and olaparib were particularly vulnerable to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Our study identifies the combination of entinostat with olaparib and doxorubicin as a new potential therapeutic approach for MYC-driven Group 3 MB.

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The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Chemical Proteomics Cal51

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