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

doi:10.1016/j.chembiol.2021.07.008

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^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

23 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 language	English (US)
Pages (from-to)	202-214.e7
Journal	Cell Chemical Biology
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2021.07.008
State	Published - Feb 17 2022

Funding

This work was supported by the NIH/NCI R01 CA181746 (to U.R.), the NIH/NCI R50 CA211447 (to H.R.L.), the V Foundation, Miles for Moffitt and the H. Lee Moffitt Cancer Center and Research Institute. We further wish to acknowledge the Moffitt Lung Cancer Center of Excellence and the Moffitt Chemical Biology (Chemistry Unit), Proteomics & Metabolomics, and Cancer Informatics Core Facilities. Moffitt Core Facilities are supported by the National Cancer Institute (award no. P30-CA076292) as a Cancer Center Support Grant. The Proteomics and Metabolomics Core is also supported by the Moffitt Foundation. Conceptualization, V.P. C.E.K. and U.R.; investigation, V.P. C.E.K. D.S.B. Y.L. X.L. S.N. E.A.W. B.F. F.K. and U.R.; formal analysis, V.P. E.A.W. and U.R.; writing – original draft, V.P. and U.R.; writing – review & editing, all authors; funding acquisition, H.R.L. and U.R.; visualization, V.P. and U.R.; supervision, J.M.K. M.S.C. H.R.L. and U.R. The authors declare no competing interests. This work was supported by the NIH / NCI R01 CA181746 (to U.R.), the NIH / NCI R50 CA211447 (to H.R.L.), the V Foundation , Miles for Moffitt and the H. Lee Moffitt Cancer Center and Research Institute . We further wish to acknowledge the Moffitt Lung Cancer Center of Excellence and the Moffitt Chemical Biology (Chemistry Unit), Proteomics & Metabolomics, and Cancer Informatics Core Facilities. Moffitt Core Facilities are supported by the National Cancer Institute (award no. P30-CA076292 ) as a Cancer Center Support Grant. The Proteomics and Metabolomics Core is also supported by the Moffitt Foundation .

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2021.07.008

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Palve, V., Knezevic, C. E., Bejan, D. S., Luo, Y., Li, X., Novakova, S., Welsh, E. A., Fang, B., Kinose, F., Haura, E. B., Monteiro, A. N., Koomen, J. M., Cohen, M. S., Lawrence, H. R., & Rix, U. (2022). The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors. Cell Chemical Biology, 29(2), 202-214.e7. https://doi.org/10.1016/j.chembiol.2021.07.008

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

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.",

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Palve, V, Knezevic, CE, Bejan, DS, Luo, Y, Li, X, Novakova, S, Welsh, EA, Fang, B, Kinose, F, Haura, EB, Monteiro, AN, Koomen, JM, Cohen, MS, Lawrence, HR & Rix, U 2022, 'The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors', Cell Chemical Biology, vol. 29, no. 2, pp. 202-214.e7. https://doi.org/10.1016/j.chembiol.2021.07.008

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AU - Palve, Vinayak

AU - Knezevic, Claire E.

AU - Bejan, Daniel S.

AU - Luo, Yunting

AU - Li, Xueli

AU - Novakova, Silvia

AU - Welsh, Eric A.

AU - Fang, Bin

AU - Kinose, Fumi

AU - Haura, Eric B.

AU - Monteiro, Alvaro N.

AU - Koomen, John M.

AU - Cohen, Michael S.

AU - Lawrence, Harshani R.

AU - Rix, Uwe

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N2 - 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.

AB - 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.

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KW - PARP inhibitor

KW - PARP1

KW - PARP16

KW - adavosertib

KW - lung cancer

KW - off-target

KW - polypharmacology

KW - proteomics

KW - talazoparib

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AN - SCOPUS:85116485796

SN - 2451-9456

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SP - 202-214.e7

JO - Cell Chemical Biology

JF - Cell Chemical Biology

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ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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