Survival of pancreatic cancer cells lacking KRAS function

• Main Authors: Noll, Elisa M. (Author), Sprick, Martin R. (Author), Trumpp, Andreas (Author), Muzumdar, Mandar (Contributor), Chen, Pan-Yu (Contributor), Dorans, Kimberly (Contributor), Chung, Katherine Minjee (Contributor), Bhutkar, Arjun (Contributor), Hong, Erin (Contributor), Jacks, Tyler E. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2017-12-11T19:48:01Z.
• Subjects: Article
• Online Access: Get fulltext

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.