Table 6.

Mechanisms of acquired resistance to proteasome inhibition

	Key components of resistance	Resistance mechanism
Mutations	Mutations in PSMB5 (gene encoding proteasome subunit β5): G322A, C323T, or both C322A/C326T A49T substitution in β5 binding pocket	Reduction in the affinity of proteasome inhibitors for the catalytically active N-terminal threonine in proteasome subunits
Overexpression of ubiquitin-proteasome pathway components	β5 and other proteasome subunits	Increase in number of binding sites for proteasome inhibitors, reducing their ability to suppress proteolysis
Activation of the aggresome–autophagy pathway	Histone deacetylase 6	Sequestration of toxic proteins in aggresomes, and activation of autophagy to promote cell survival
Heat shock protein (HSP) induction	HSP70, HSP90 and other HSP family members	Enhanced protein chaperone capabilities, thereby maintaining protein homeostasis and reducing proteotoxic stress; increased threshold for apoptosis
Growth factor induction	Overexpression of IGF‐1/IGF-1R pathway components	Activation of antiapoptotic signalling through AKT
Antioxidant response pathway induction	Overexpression of NFE2L2 (gene encoding nuclear factor erythroid 2-related factor 2)	Promotes proteasome assembly through induction of proteasome maturation protein (POMP)
Plasma cell differentiation	Reduced expression of IRE1 and XBP-1	Decreased immunoglobulin synthesis and proteotoxic stress, thereby reducing proapoptotic activity of proteasome inhibitors
EGFR/JAK/STAT signaling	Expression levels of tight junction protein 1 (ZO-1), which suppresses EGFR signaling	Induction of signalling linked with increased expression of proteasome subunits