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

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): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung Neuroendocrine Cell

DISEASE(S): Lung Small Cell Carcinoma

SUBMITTER: John Koomen  

LAB HEAD: Uwe Rix, PhD

PROVIDER: PXD020484 | Pride | 2021-07-21

REPOSITORIES: Pride