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. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.

• • Spella, M.

Ntaliarda, G.

Skiadas, G.

Lamort, A. S.

Vreka, M.

Marazioti, A.

Lilis, I.

Bouloukou, E.

Giotopoulou, G. A.

Pepe, M. A. A.

Weiss, S. A. I.

Petrera, A.

Hauck, S. M.

Koch, I.

Lindner, M.

Hatz, R. A.

Behr, J.

Arendt, K. A. M.

Giopanou, I.

Brunn, D.

Savai, R.

Jenne, D. E.

de Château, M.

Yull, F. E.

Blackwell, T. S.

Stathopoulos, G. T.