The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors

Vinayak Palve, Claire E. Knezevic, Daniel S. Bejan, Yunting Luo, Xueli Li, Silvia Novakova, Eric A. Welsh, Bin Fang, Fumi Kinose, Eric B. Haura, Alvaro N. Monteiro, John M. Koomen, Michael S. Cohen, Harshani R. Lawrence, Uwe Rix

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells. Chemical proteomics identifies PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition. Drug combination screening reveals talazoparib synergy with the WEE1/PLK1 inhibitor adavosertib. Global phosphoproteomics identifies disparate effects on cell-cycle and DNA damage signaling thereby illustrating underlying mechanisms of synergy, which is more pronounced for talazoparib than olaparib. Notably, silencing PARP16 further reduces cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib's overall mechanism of action and constitutes an actionable target in SCLC.

Original languageEnglish (US)
Pages (from-to)202-214.e7
JournalCell Chemical Biology
Volume29
Issue number2
DOIs
StatePublished - Feb 17 2022
Externally publishedYes

Keywords

  • Ewing's sarcoma
  • PARP inhibitor
  • PARP1
  • PARP16
  • adavosertib
  • lung cancer
  • off-target
  • polypharmacology
  • proteomics
  • talazoparib

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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