Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion

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 alpha-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1 beta. Indeed, IKK alpha is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-kappa B signaling. IL-1 beta fuels addiction of mutant KRAS to IKK alpha resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1 beta-mediated NF-kappa 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 alpha, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKK alpha-mediated responsiveness of tumor cells to host IL-1 beta, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.