A genome-scale CRISPR screen identifies the ERBB and mTOR signalling networks as key determinants of response to PI3K inhibition in pancreatic cancer

Abstract

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