A Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer

摘要: KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity an additional requirement for Kras-induced tumorigenesis. Clinical trials inhibitors in have shown limited responses. Understanding the molecular basis this lack efficacy may direct future treatment strategies with emerging inhibitors. We sought new therapeutic approaches that synergize through pooled CRISPR modifier genetic screening drug combination screen. ERBB family receptor tyrosine kinase signaling mTOR were modifiers sensitivity to alpelisib pictilisib. Inhibition or was synergistic inhibition spheroid, stromal cocultures. Near-complete loss ribosomal S6 phosphorylation associated synergy. Genetic alterations ERBB-PI3K axis decreased survival patients cancer. Suppression PI3K/mTOR potentiated by dual inhibition. Surprisingly, despite presence oncogenic KRAS, thought bestow independence from signaling, blocks downstream activation synergizes Further exploration these combinations warranted