Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma.
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Authors
Caumanns, Joseph J
Berns, Katrien
Wisman, G Bea A
Fehrmann, Rudolf SN
Tomar, Tushar
Klip, Harry
Meersma, Gert J
Hijmans, E Marielle
Gennissen, Annemiek MC
Duiker, Evelien W
Weening, Desiree
Itamochi, Hiroaki
Kluin, Roelof JC
Reyners, Anna KL
Birrer, Michael J
Salvesen, Helga B
Vergote, Ignace
van Nieuwenhuysen, Els
Brenton, James
Braicu, E Ioana
Kupryjanczyk, Jolanta
Spiewankiewicz, Beata
Mittempergher, Lorenza
Bernards, René
van der Zee, Ate GJ
Publication Date
2018-08-15Journal Title
Clin Cancer Res
ISSN
1078-0432
Publisher
American Association for Cancer Research (AACR)
Volume
24
Issue
16
Pages
3928-3940
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Caumanns, J. J., Berns, K., Wisman, G. B. A., Fehrmann, R. S., Tomar, T., Klip, H., Meersma, G. J., et al. (2018). Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma.. Clin Cancer Res, 24 (16), 3928-3940. https://doi.org/10.1158/1078-0432.CCR-17-3060
Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient-derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928-40. ©2018 AACR.
Keywords
Adenocarcinoma, Clear Cell, Animals, Cell Line, Tumor, Cell Proliferation, Class I Phosphatidylinositol 3-Kinases, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Morpholines, Mutation, Nuclear Proteins, Ovarian Neoplasms, Signal Transduction, Transcription Factors
Sponsorship
Cancer Research UK (CB4150)
Cancer Research UK (A15601)
Identifiers
External DOI: https://doi.org/10.1158/1078-0432.CCR-17-3060
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280097
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