PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

Yang Li; Lacey E. Dobrolecki; Christina Sallas; Xudong Zhang; Travis D. Kerr; Deepa Bisht; Yalong Wang; Sharad Awasthi; Babita Kaundal; Siqi Wu; Weiyi Peng; Marc L. Mendillo; Yiling Lu; Collene R. Jeter; Guang Peng; Jinsong Liu; Shannon N. Westin; Anil K. Sood; Michael T. Lewis; Jishnu Das; S. Stephen Yi; Mark T. Bedford; Daniel J. McGrail; Nidhi Sahni

doi:10.1016/j.xcrm.2023.101326

PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu DasS. Stephen Yi, Mark T. Bedford, Daniel J. McGrail^*, Nidhi Sahni^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

4 Scopus citations

Abstract

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

Original language	English (US)
Article number	101326
Journal	Cell Reports Medicine
Volume	4
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2023.101326
State	Published - Dec 19 2023

Funding

N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021, a recipient of the Early Career Award by Ovarian Cancer Research Alliance (grant 649968); the Blanton-Davis Ovarian Cancer Research Program; and the Andrew Sabin Family Foundation Fellowship. Funding support to D.J.M. was provided by Susan G. Komen grant PDF17483544. Additional funding was provided by Susan G. Komen Foundation grant CCR19609287 (S.S.Y.); NIH R35GM133658 (S.S.Y.); NCI CA16672 (RPPA Core Facilities/Y. Lu); NIH R50CA221675 (Y. Lu); NIH R35GM137836 (N.S.); CPRIT Core Facility Grant RP170628 (Flow Cytometry and Imaging Core Facilities/C.R.J.); NCI CA125123 (M.T.L. L.E.D. C.S.); CPRIT Core Facilities Support Grant RP170691 (M.T.L. L.E.D. C.S.); CPRIT RP200520 (W.P.); SPORE in Ovarian Cancer (CA216785); Ovarian Cancer Moon Shot (A.K.S.); the American Cancer Society (A.K.S.); the Frank McGraw Memorial Chair in Cancer Research (A.K.S.); and US Department of Defense Breast Cancer Research Program W81XWH2210018 (M.L.M.). Y. Li, L.E.D. C.S. T.D.K. D.B. Y.W. S.A. B.K. S.W. Y. Lu, C.R.J. and D.J.M. performed experiments and compiled experimental data. X.Z. and J.L. developed organoid models. W.P. M.L.M. G.P. S.N.W. A.K.S. M.T.L. J.D. S.S.Y. and M.T.B provided guidance on data interpretation, analysis, and project direction. M.T.B. D.J.M. and N.S. conceptualized the project. D.J.M. and N.S. wrote the manuscript with critical input from all authors. D.J.M. and N.S. supervised the project. M.T.L. is a founder and limited partner in StemMed, Ltd. and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics, Inc. Some PDXs are exclusively licensed to StemMed, Ltd. resulting in royalty income to M.T.L. L.E.D. is a compensated employee of StemMed, Ltd. Some PDXs are exclusively licensed to StemMed, Ltd. resulting in royalty income to L.E.D. A.K.S. discloses the following competing interests: consulting (Merck, GSK, ImmunoGen, Iylon, Kiyatec, Astra Zeneca, Onxeo), shareholder (BioPath), and patent (EGFL6 antibody). N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 , a recipient of the Early Career Award by Ovarian Cancer Research Alliance (grant 649968 ); the Blanton-Davis Ovarian Cancer Research Program; and the Andrew Sabin Family Foundation Fellowship. Funding support to D.J.M. was provided by Susan G. Komen grant PDF17483544 . Additional funding was provided by Susan G. Komen Foundation grant CCR19609287 (S.S.Y.); NIH R35GM133658 (S.S.Y.); NCI CA16672 (RPPA Core Facilities/Y. Lu); NIH R50CA221675 (Y. Lu); NIH R35GM137836 (N.S.); CPRIT Core Facility Grant RP170628 (Flow Cytometry and Imaging Core Facilities/C.R.J.); NCI CA125123 (M.T.L., L.E.D., C.S.); CPRIT Core Facilities Support Grant RP170691 (M.T.L., L.E.D., C.S.); CPRIT RP200520 (W.P.); SPORE in Ovarian Cancer ( CA216785 ); Ovarian Cancer Moon Shot (A.K.S.); the American Cancer Society (A.K.S.); the Frank McGraw Memorial Chair in Cancer Research (A.K.S.); and US Department of Defense Breast Cancer Research Program W81XWH2210018 (M.L.M.).

Keywords

DNA replication stress
PARP inhibitors
PRMT inhibitors
arginine methylation
breast cancer
ovarian cancer

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

Access to Document

10.1016/j.xcrm.2023.101326

Cite this

Li, Y., Dobrolecki, L. E., Sallas, C., Zhang, X., Kerr, T. D., Bisht, D., Wang, Y., Awasthi, S., Kaundal, B., Wu, S., Peng, W., Mendillo, M. L., Lu, Y., Jeter, C. R., Peng, G., Liu, J., Westin, S. N., Sood, A. K., Lewis, M. T., ... Sahni, N. (2023). PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition. Cell Reports Medicine, 4(12), Article 101326. https://doi.org/10.1016/j.xcrm.2023.101326

@article{946a7226f2ba4926bae689c125828b63,

title = "PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition",

abstract = "Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.",

keywords = "DNA replication stress, PARP inhibitors, PRMT inhibitors, arginine methylation, breast cancer, ovarian cancer",

author = "Yang Li and Dobrolecki, {Lacey E.} and Christina Sallas and Xudong Zhang and Kerr, {Travis D.} and Deepa Bisht and Yalong Wang and Sharad Awasthi and Babita Kaundal and Siqi Wu and Weiyi Peng and Mendillo, {Marc L.} and Yiling Lu and Jeter, {Collene R.} and Guang Peng and Jinsong Liu and Westin, {Shannon N.} and Sood, {Anil K.} and Lewis, {Michael T.} and Jishnu Das and Yi, {S. Stephen} and Bedford, {Mark T.} and McGrail, {Daniel J.} and Nidhi Sahni",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = dec,

day = "19",

doi = "10.1016/j.xcrm.2023.101326",

language = "English (US)",

volume = "4",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "12",

}

Li, Y, Dobrolecki, LE, Sallas, C, Zhang, X, Kerr, TD, Bisht, D, Wang, Y, Awasthi, S, Kaundal, B, Wu, S, Peng, W, Mendillo, ML, Lu, Y, Jeter, CR, Peng, G, Liu, J, Westin, SN, Sood, AK, Lewis, MT, Das, J, Yi, SS, Bedford, MT, McGrail, DJ & Sahni, N 2023, 'PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition', Cell Reports Medicine, vol. 4, no. 12, 101326. https://doi.org/10.1016/j.xcrm.2023.101326

TY - JOUR

T1 - PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

AU - Li, Yang

AU - Dobrolecki, Lacey E.

AU - Sallas, Christina

AU - Zhang, Xudong

AU - Kerr, Travis D.

AU - Bisht, Deepa

AU - Wang, Yalong

AU - Awasthi, Sharad

AU - Kaundal, Babita

AU - Wu, Siqi

AU - Peng, Weiyi

AU - Mendillo, Marc L.

AU - Lu, Yiling

AU - Jeter, Collene R.

AU - Peng, Guang

AU - Liu, Jinsong

AU - Westin, Shannon N.

AU - Sood, Anil K.

AU - Lewis, Michael T.

AU - Das, Jishnu

AU - Yi, S. Stephen

AU - Bedford, Mark T.

AU - McGrail, Daniel J.

AU - Sahni, Nidhi

PY - 2023/12/19

Y1 - 2023/12/19

N2 - Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

AB - Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

KW - DNA replication stress

KW - PARP inhibitors

KW - PRMT inhibitors

KW - arginine methylation

KW - breast cancer

KW - ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=85180336055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85180336055&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2023.101326

DO - 10.1016/j.xcrm.2023.101326

M3 - Article

C2 - 38118413

AN - SCOPUS:85180336055

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 101326

ER -

PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this