Myeloid-derived interleukin-1? drives oncogenic KRAS-NF-?? addiction in malignant pleural effusion.

ABSTRACT: Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKK?-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1?. Indeed, IKK? is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-?B signaling. IL-1? fuels addiction of mutant KRAS to IKK? resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1?-mediated NF-?B induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKK?, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKK?-mediated responsiveness of tumor cells to host IL-1?, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.

SUBMITTER: Marazioti A 

PROVIDER: S-EPMC5813197 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature