RT Journal Article SR Electronic T1 An in vivo inflammatory loop potentiates KRAS blockade JF bioRxiv FD Cold Spring Harbor Laboratory SP 629139 DO 10.1101/629139 A1 Kristina A.M. Arendt A1 Giannoula Ntaliarda A1 Vasileios Armenis A1 Danai Kati A1 Christin Henning A1 Georgia A. Giotopoulou A1 Mario A.A. Pepe A1 Laura V. Klotz A1 Anne-Sophie Lamort A1 Rudolf A. Hatz A1 Sebastian Kobold A1 Georgios T. Stathopoulos YR 2019 UL http://biorxiv.org/content/early/2019/05/07/629139.abstract AB KRAS inhibitors perform inferior to other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom-designed vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens since the latter drugs function to suppress interleukin-1 receptor 1 expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover the findings support that interleukin-1β blockade might be suitable for the therapy of KRAS-mutant cancers.