Table 6.
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 |