The proteasome inhibitor bortezomib has shown remarkable clinical success in the 
treatment of multiple myeloma. However, the efficacy and mechanism of action of 
bortezomib in solid tumor malignancies is less well understood. In addition, the 
use of this first-in-class proteasome inhibitor is limited by several factors, 
including off-target effects that lead to adverse toxicities. We recently 
reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class 
proteasome inhibitors with higher specificities and reduced toxicities, against 
head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib 
potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both 
compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which 
serves to mediate and attenuate, respectively, the killing activities of these 
proteasome inhibitors. Both compounds also induce complete autophagic flux that 
is partially dependent on activation of the unfolded protein response (UPR) and 
upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to 
promote HNSCC cell survival. Our study indicates that the therapeutic benefit of 
these promising proteasome inhibitors may be improved by inhibiting MCL1 
expression or autophagy.