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Open AccessArticle

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

1
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Torino, Italy
2
Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy
3
Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
4
Città della Salute e della Scienza, 10126 Torino, Italy
5
Department of Life Sciences and Systems Biology, University of Torino, 10125 Torino, Italy
6
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
7
University of Cambridge, Cambridge CB2 0XZ, UK
8
Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cells 2020, 9(2), 442; https://doi.org/10.3390/cells9020442 (registering DOI)
Received: 7 November 2019 / Revised: 4 February 2020 / Accepted: 13 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Ovarian Cancer)
Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.
Keywords: ovarian cancer; PI3K; PIK3R1; Patient-Derived xenografts; PDX derived tumour cells ovarian cancer; PI3K; PIK3R1; Patient-Derived xenografts; PDX derived tumour cells
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D’Ambrosio, C.; Erriquez, J.; Arigoni, M.; Capellero, S.; Mittica, G.; Ghisoni, E.; Borella, F.; Katsaros, D.; Privitera, S.; Ribotta, M.; Maldi, E.; Di Nardo, G.; Berrino, E.; Venesio, T.; Ponzone, R.; Vaira, M.; Hall, D.; Jimenez-Linan, M.; Paterson, A.L.; Calogero, R.A.; Brenton, J.D.; Valabrega, G.; Di Renzo, M.F.; Olivero, M. PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma. Cells 2020, 9, 442.

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