An in vivo inflammatory loop potentiates KRAS blockade

inhibitors perform inferior to other targeted drugs 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 KRAS), and silenced/overexpressed mutant KRAS using custom-designed vectors. We show that -mutant tumor cells exclusively respond to KRAS blockade , 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, -mutant tumors did not respond to deltarasin in and gene-deficient mice, but were deltarasin-sensitive in wild-type and -deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high mutation prevalence and predicted poor survival. Our findings support that 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 . Moreover the findings support that interleukin-1β blockade might be suitable for the therapy of -mutant cancers.