Dataset Information

Global Phosphoproteomics of BRCA1-deficient mammary tumors in genetic mouse models

ABSTRACT: The aim of the study is to identify differences in the global phosphoproteome across a BRCA1-deficient mouse mammary tumor panel. We have matched PARPi-naive and PARPi-resistant tumors, in which resistance was induced in vivo (mice bearing tumors were treated with PARPi untill the tumors stopped responding). Each pair of matched naive/resistant tumors originate from a different original tumor donor (one can consider each individual donor as an individual patient). From another analysis (RAD51 IRIF) we know that the mechanism of PARPi-resistance in a number of the tumors is driven by alterations in DNA damage response. Therefore, we can divide the tumors into four groups: (A) HR proficient, the exact mechanism not known, (B) HR proficient due to the loss of 53bp1 (TP53BP1), (C) HR proficient due to loss of Rev7 (MAD2L2) and (D) HR deficient, mechanism of resistance not known. Additionally, each tumor from our panel was retransplanted and challenged with 15 Gy irradiation to trigger a DNA damage response, therefore for each tumor we have an irradiated (IR) and a non-irradiated (NIR) sample. In this experiment each sample was processed in duplicate. Given all this, group (A) consists of 6 individual donors x 2 (matched naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 48 samples (samples 1-48); groups (B)-(D): 2 donors (per group) x 2 (naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 16 samples/group (B: samples 65-80, C: samples 81-96 and D: 49-64, according to the OPL label). In total this gives: 48 + 16 +16 +16 = 96 samples. Part of this analysis is used in the paper that also describes data from PXD031711

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Mammary Epithelial Cell, Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Sander Piersma

LAB HEAD: Connie Jimenez

PROVIDER: PXD032007 | Pride | 2022-06-06

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	MQ_TXT_KB1P_mouse_TiOx.zip	Other
	Mouse_tumor_phosphosites_table.xlsx	Xlsx
	QE2_150602_OPL1005_EG_TiOx_BRCA_mouse_01.raw	Raw
	QE2_150602_OPL1005_EG_TiOx_BRCA_mouse_02.raw	Raw
	QE2_150602_OPL1005_EG_TiOx_BRCA_mouse_03.raw	Raw

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Publications

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Zingg Daniel D Bhin Jinhyuk J Yemelyanenko Julia J Kas Sjors M SM Rolfs Frank F Lutz Catrin C Lee Jessica K JK Klarenbeek Sjoerd S Silverman Ian M IM Annunziato Stefano S Chan Chang S CS Piersma Sander R SR Eijkman Timo T Badoux Madelon M Gogola Ewa E Siteur Bjørn B Sprengers Justin J de Klein Bim B de Goeij-de Haas Richard R RR Riedlinger Gregory M GM Ke Hua H Madison Russell R Drenth Anne Paulien AP van der Burg Eline E Schut Eva E Henneman Linda L van Miltenburg Martine H MH Proost Natalie N Zhen Huiling H Wientjens Ellen E de Bruijn Roebi R de Ruiter Julian R JR Boon Ute U de Korte-Grimmerink Renske R van Gerwen Bastiaan B Féliz Luis L Abou-Alfa Ghassan K GK Ross Jeffrey S JS van de Ven Marieke M Rottenberg Sven S Cuppen Edwin E Chessex Anne Vaslin AV Ali Siraj M SM Burn Timothy C TC Jimenez Connie R CR Ganesan Shridar S Wessels Lodewyk F A LFA Jonkers Jos J

Nature 20220810 7923

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the ...[more]

PMID: 35948633

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Project description:Extending the therapeutic spectrum of PARP-inhibition (PARPi) beyond HR-deficiency or reverting PARPi resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a promising strategy for defining new therapeutic standards. In this study, we analysed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with PARPi. This is the first study analysing the potential therapeutic effect of these components. In vitro assays for drug characterization including RNA-seq were applied in a selected panel of ovarian cancer cell lines. CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the micro- to almost millimolar range (107-940µM), whereas its metabolite CT913-M1 was about 10-fold more potent (IC50 of 17-93µM). Neither of the drugs increased the cytotoxic effect of cisplatin, CT913 might even antagonize it. Furthermore, CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that homologues recombination (HR) repair may contribute to its mechanism of action. Importantly, CT913 sensitized for olaparib treatment, independently of BRCA-1 mutational status, supporting the finding that CT913 may act partially independent of an impaired HR. CT913 treatment led to changes in gene transcription. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It also downregulated a variety of transcripts involved in prominent DNA-repair pathways, such as HR, mismatch repair (MMR) or nucleotide excision repair (NER). This is the first study, suggesting the triazene drug class CT913 as auxiliary drug for extending the therapeutic spectrum of PARPi.