Abstract
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.
Highlights
Epithelial Ovarian Cancer (EOC) is a heterogeneous disease with five major histologic types [1].The most frequent is high grade serous epithelial ovarian cancer (EOC) (HGS-EOC), characterized by disruption of TP53 [2].The majority of patients with high grade serous EOC (HGS-EOC) present with advanced stage disease and there has been little improvement in overall survival with standard treatment, which has not changed over the past 20 years and relies on cytoreductive surgery and platinum-based combination chemotherapy [3].Maintenance therapy with inhibitors of the Poly (ADP-ribose) polymerase (PARP) offers significant survival advantages for patients with BRCA1 and BRCA2 mutations [4,5], but targeted therapy for other HGS-EOC patients is much less developed compared to other solid tumours
Patient-Derived Xenografts (PDXs) lines derived from epithelial ovarian carcinomas were fully characterized
We demonstrate here that a rare mutation in the PIK3R1 tumour suppressor gene [29] is actionable in HGS-EOC using validated patient-derived models of the disease
Summary
Epithelial Ovarian Cancer (EOC) is a heterogeneous disease with five major histologic types [1].The most frequent is high grade serous EOC (HGS-EOC), characterized by disruption of TP53 [2].The majority of patients with HGS-EOC present with advanced stage disease and there has been little improvement in overall survival with standard treatment, which has not changed over the past 20 years and relies on cytoreductive surgery and platinum-based combination chemotherapy [3].Maintenance therapy with inhibitors of the Poly (ADP-ribose) polymerase (PARP) offers significant survival advantages for patients with BRCA1 and BRCA2 mutations [4,5], but targeted therapy for other HGS-EOC patients is much less developed compared to other solid tumours. In melanoma and non-small cell lung carcinomas, specific genetic alterations have been identified as key oncogenic drivers, i.e., as mutations able to confer a selective advantage to a cell, through either increasing its survival or proliferation and, able to cause clonal expansion of the carrier cell. These findings have led to the development of therapies targeting these mutations, which has provided demonstrable clinical benefit [6]. A number of these mutations have been defined as “actionable”, because their functional outcome makes carrier cells responsive to a targeted therapy, and thanks to the availability of a specific targeted drug
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