Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. The aim of this study was to investigate the pathways through which KRAS-mutant cancers foster their growth, thereby unravelling novel therapeutic targets. We show that KRAS-mutant tumors secrete the protein versican, which then drives the activation of NF-kappa B kinase (IKK) beta in a type of host immune cells called macrophages. Following this activation, macrophages fuel the tumor with interleukin (IL)-1 beta, to close an inflammatory loop through which KRAS-mutant cancers attract host immune cells to the tumor site to accelerate tumor growth and aggressiveness. Importantly, we show that targeting IL-1 beta and/or versican can be an effective treatment for KRAS-mutant cancers, holding great promise for cancer patients.Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1 beta and nuclear factor (NF)-kappa B inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1 beta via inflammatory versican signaling to macrophage inhibitor of NF-kappa B kinase (IKK) beta. Human pan-cancer and experimental NF-kappa B reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKK beta activation and IL-1 beta release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKK beta deletion prevents myeloid NF-kappa B activation and metastasis. Versican and IKK beta are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1 beta addiction is abolished by IL-1 beta and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKK beta in metastasis.