Significance
NF-κB has been implicated in many inflammatory and malignant diseases, such as MM. Yet therapeutically targeting this pathway has proved an insurmountable challenge. The conundrum with current strategies has been how to block NF-κB in a disease-specific manner, given NF-κB’s pleiotropic and ubiquitous functions. Here, we have achieved this goal in the context of MM. Rather than targeting NF-κB, we targeted the downstream module, GADD45β/MKK7, within a pathogenically critical and cancer-restricted axis of the NF-κB pathway. We demonstrate that agents targeting this axis are both highly effective against MM and well tolerated in vivo, with far greater cancer cell specificity than global NF-κB inhibitors. Plausibly, the same principle could be applied for targeting NF-κB disease selectively also in pathologies beyond MM.

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