Proteomics

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LC-MS/MS identification of differentially expressed proteins in carboplatin resistant Triple Negative Breast Cancer


ABSTRACT: Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Adenocarcinoma Cell Line, Mammary Gland

DISEASE(S): Triple-receptor Negative Breast Cancer

SUBMITTER: Delphi Van Haver  

LAB HEAD: Frederic Amant

PROVIDER: PXD021726 | Pride | 2021-07-07

REPOSITORIES: Pride

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Publications

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

Moens Stijn S   Zhao Peihua P   Baietti Maria Francesca MF   Marinelli Oliviero O   Van Haver Delphi D   Impens Francis F   Floris Giuseppe G   Marangoni Elisabetta E   Neven Patrick P   Annibali Daniela D   Sablina Anna A AA   Amant Frédéric F  

Scientific reports 20210204 1


Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based  ...[more]

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