Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy

Abstract

Over the past decade, inhibition of the kinase activities of oncogenic proteins using small molecules and antibodies has been a mainstay of our anticancer drug development effort, resulting in several Food and Drug Administration-approved cancer therapies. The clinical effectiveness of kinase-targeted agents has been inconsistent, mostly because of the development of resistance. The expression and function of oncoproteins and tumor suppressors are regulated by numerous posttranslational protein modifications including phosphorylation, ubiquitination, and acetylation; hence, targeting specific posttranslational protein modifications provides for an attractive strategy for anticancer drug development. The present review discusses the hypothesis that targeted degradation of an oncoprotein may overcome many of the shortcomings seen with kinase inhibitors and that the approach would enable targeted inhibition of oncogenic proteins previously thought to be undruggable.

Figure 1

Disruption of protein-protein interactions to induce oncoproteins degradation. (A) Disruptin (D), a peptide containing an eight–amino acid stretch of human EGFR, is capable of disrupting the protein:protein interactions between EGFR:HSP90 and EGFR homodimers. These interactions are critical for maintaining EGFR stability. In the presence of high levels of EGF, as seen in the tumor microenvironment, treatment with Disruptin causes rapid degradation of EGFR. In preclinical models, treatment with Disruptin induces regression of EGFR-dependent tumors including those resistant to TKIs. (B) Interaction between the SMURF2:UBCH5 protein complex and β-TrCP1 plays a critical role in the maintenance of KRAS protein stability. The SMURF2:UBCH5 complex polyubiquitinates and degrades β-TrCP1, which indirectly protects KRAS from degradation. We found that the disruption of the SMURF2:UBCH5 complex can promote β-TrCP1 accumulation, leading to rapid KRAS degradation.