Survival of pancreatic cancer cells lacking KRAS function
October 23, 2017
50 nL of compounds were pin-transferred (V&P Scientific pin tool mounted onto a Tecan Freedom Evo 150 MCA96 head) into duplicate assay plates and incubated for 72 h. The DMSO content was 0.1% within each well.
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.
Muzumdar, MD; Chen, PY; Dorans, KJ; Chung, KM; Bhutkar, A; Hong, E; Noll, EM; Sprick, MR; Trumpp, A; Jacks, T;
Journal: Nat Commun
Original article (29061961)