Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition

被引:13
作者
Aziz, Diar [1 ,2 ,3 ,4 ]
Portman, Neil [5 ,6 ]
Fernandez, Kristine J. [5 ]
Lee, Christine [5 ]
Alexandrou, Sarah [5 ]
Llop-Guevara, Alba [7 ]
Phan, Zoe [5 ]
Yong, Aliza [5 ]
Wilkinson, Ashleigh [5 ]
Sergio, C. Marcelo [5 ]
Ferraro, Danielle [1 ,2 ]
Etemadmoghadam, Dariush [3 ]
Bowtell, David D. [3 ]
Serra, Violeta [7 ]
Waring, Paul [1 ,2 ]
Lim, Elgene [5 ,6 ]
Caldon, C. Elizabeth [5 ,6 ]
机构
[1] Univ Melbourne, Ctr Translat Pathol, Dept Pathol, Parkville, Vic, Australia
[2] Univ Melbourne, Dept Surg, Parkville, Vic, Australia
[3] Peter MacCallum Canc Inst, Victorian Comprehens Canc Ctr, Parkville, Vic, Australia
[4] Univ Mosul, Coll Med, Pathol Dept, Mosul, Iraq
[5] Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia
[6] UNSW Sydney, St Vincents Clin Sch, Fac Med, Sydney, NSW, Australia
[7] Vall dHebron Inst Oncol, Expt Therapeut Grp, Barcelona, Spain
[8] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
REQUIRES CYCLIN D1; EXPRESSION; E2; PROLIFERATION; PROGNOSIS; GROWTH; REPAIR;
D O I
10.1038/s41523-021-00312-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
引用
收藏
页数:14
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