Mechanisms of resistance and susceptibility to proteasome inhibition. Signaling through canonical or noncanonical pathways leads to phosphorylation, ubiquitination, and subsequent degradation of the IkB kinases through the proteasome pathway, resulting in NFkB translocation to the nucleus and transcription of target genes. Constitutive NFkB signaling can result from mutations in regulatory genes, such as Traf3, leading to increased sensitivity of the cell to proteasome inhibition. Mechanisms of resistance include: (1) the 26S proteasome acquiring resistance due to mutations or overexpression of the PSMB5 subunit; (2) proteasome inhibitors being antagonized by upregulation of heat shock proteins, such as Hsp27; and (3) increased activity of the aggresome pathway. These resistance mechanisms can be targeted to increase the efficacy of proteasome inhibition.