Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes
A partir d'échantillons tumoraux prélevés sur 44 patients atteints d'un carcinome à cellules acineuses du pancréas, cette étude identifie plusieurs anomalies génomiques susceptibles de faire l'objet de thérapies ciblées, notamment des inhibiteurs de MEK ou de PARP
Pancreatic acinar cell carcinomas (PACCs) account for ~1% (~500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiation have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in ~23% of tumors. The most prevalent fusion, SND1-BRAF, results in activation of the mitogen activated protein kinase (MAPK) pathway which can be abrogated with MEK inhibition. SND1-BRAF transformed cells were sensitive to treatment with the MEK inhibitor, trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations (GAs) causing inactivation of DNA repair genes (45%); these GAs have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable GAs in the majority of PACCs, and provide a rationale for using personalized therapies in this disease.