PIK3R1 W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 2
• Main Authors: D'Ambrosio, Concetta, Erriquez, Jessica, Arigoni, Maddalena, Capellero, Sonia, Mittica, Gloria, Ghisoni, Eleonora, Borella, Fulvio, Katsaros, Dionyssios, Privitera, Silvana, Ribotta, Marisa, Maldi, Elena, Di Nardo, Giovanna, Berrino, Enrico, Venesio, Tiziana, Ponzone, Riccardo, Vaira, Marco, Hall, Douglas, Jimenez-Linan, Mercedes, Paterson, Anna L, Calogero, Raffaele A, Brenton, James D, Valabrega, Giorgio, Di Renzo, Maria Flavia, Olivero, Martina
• Format: Journal Article
• Language: English
• Published: Switzerland 14.02.2020
• Subjects: Animals; Carcinoma, Ovarian Epithelial - drug therapy; Carcinoma, Ovarian Epithelial - enzymology; Carcinoma, Ovarian Epithelial - genetics; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - enzymology; Cystadenocarcinoma, Serous - genetics; Female; Heterografts; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Mutation; Neoplasm Grading; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Random Allocation; PI3K; ovarian cancer; PDX derived tumour cells; Patient-Derived xenografts; PIK3R1
• ISSN: 2073-4409

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 variant in PDXs from a high grade serous EOC. Allele frequencies of 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 and addiction of carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The 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.