Synthetic lethality with PI3K inhibition in EBV associated Gastric Cancer

Gastric cancer is the third leading cause of cancer death, responsible for over 1 million new cases per year. The Cancer Genome Atlas (TCGA) identified that EBV infects nearly 10% of all gastric carcinomas and provides compelling evidence that EBV-associated gastric cancer (EBVaGC) differs from other gastric cancer subtypes. TCGA identified that PI3 kinase (PI3K) gain-of-function mutations occur in >80% of EBVaGC. Since mutations are observed in the PI3K negative regulator PTEN in other cases and likely also in other PI3K regulators, we hypothesize that PI3K hyperactivation may be obligatory in EBVaGC. This suggests that FDA-approved class I PI3K inhibitors may have efficacy in treatment of EBVaGC. However, their use has been limited by dose-related toxicities. Nonetheless, there had remained a lack of systematic genetic studies to functionally characterize any of the key aspects of EBVaGC, including the intriguingly high occurrence of PI3K mutations, to support alternative PI3K-based therapeutic approaches. To gain insights into EBVaGC dependencies on hyperactive PI3K signaling, we performed a human genome-wide CRISPR/Cas9 screen to identify EBVaGC targets whose inhibition is synthetic lethal with low dose PI3K blockade.