Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis

Abstract

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging "Achilles heel" of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.

Keywords: autophagy; chemoresistance; multiple myeloma; proteasome; protein quality control; proteotoxic stress; triple negative breast cancer; unfolded protein response.

Figure 1

Protein handling pathways in cancer cells. cancer cells have to cope with a large burden of misfolded proteins, which if not managed appropriately results in endoplasmic reticulum (ER) stress and eventual cell death. As such, cancer cells are highly dependent on a tightly regulated network of protein quality control pathways such as (A) the ubiquitin proteasome system (UPS), (B) macroautophagy, (C) aggresome formation, (D) heat shock response, and (E) the unfolded protein response.

Figure 2

Hijacking the ubiquitin proteasome system (UPR) for targeted protein degradation. Targeted protein degradation has recently emerged as an attractive and promising approach against currently undruggable (and druggable) targets. (A) the PROteolysis Targeting Chimera (PROTAC) system: PROTACs are heterobifunctional molecules that serves as a bridge by binding to an E3 ligase on one side and to the protein of interest on the other, thereby facilitating polyubiquitination and proteasome degradation of the protein of interest. (B) deronimids are specifically modified immunomodulatory drugs (IMiDs) that recruit the Cereblon E3 ubiquitin ligase to the protein of interest to facilitate target proteasome degradation. (C) TRIM21 is an E3 ubiquitin ligase that recognizes and polyubiquitinates antibody-bound substrates by binding with high affinity to the Fc domain of antibodies.