Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

被引：11

作者：

Pogacar, Ziva ^{[1
]}

Johnson, Jackie L. ^{[1
]}

Krenning, Lenno ^{[2
]}

De Conti, Giulia ^{[1
]}

Jochems, Fleur ^{[1
]}

Lieftink, Cor ^{[3
]}

Velds, Arno ^{[4
]}

Wardak, Leyma ^{[1
]}

Groot, Kelvin ^{[1
]}

Schepers, Arnout ^{[1
]}

Wang, Liqin ^{[1
]}

Song, Ji-Ying ^{[5
]}

van de Ven, Marieke ^{[6
]}

van Tellingen, Olaf ^{[7
]}

Medema, Rene H. ^{[2
]}

Beijersbergen, Roderick L. ^{[1
,3
]}

Bernards, Rene ^{[1
]}

de Oliveira, Rodrigo Leite ^{[1
,8
]}

机构：

[1] Netherlands Canc Inst, Oncode Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands

[2] Netherlands Canc Inst, Oncode Inst, Div Cell Biol, Amsterdam, Netherlands

[3] Netherlands Canc Inst, NKI Robot & Screening Ctr, Amsterdam, Netherlands

[4] Netherlands Canc Inst, Genom Core Facil, Amsterdam, Netherlands

[5] Netherlands Canc Inst, Div Anim Pathol, Amsterdam, Netherlands

[6] Netherlands Canc Inst, Mouse Clin Canc & Aging, Amsterdam, Netherlands

[7] Netherlands Canc Inst, Div Pharmacol, Amsterdam, Netherlands

[8] Univ Amsterdam, CRISPR Expertise Ctr, Canc Ctr Amsterdam, Med Ctr, Amsterdam, Netherlands

来源：

PLOS ONE | 2022年 / 17卷 / 09期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

SULFONAMIDE ANTICANCER AGENT; CELL-CYCLE; PHASE-I; CDK4/6; INHIBITION; BREAST-CANCER; E7070; PHOSPHORYLATION; RESISTANCE; SCHEDULE; DECISION;

D O I：

10.1371/journal.pone.0273182

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.

引用

页数：23

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