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.

Multiple myeloma (MM) is a plasma cell cancer characterized by sustained endoplasmic reticulum (ER) stress and unfolded protein response activation in the setting of high rates of immunoglobulin synthesis. Consequently, MM cells rely heavily on protein quality control pathways for survival as evidenced by the clinical efficacy of proteasome inhibitors (PI). Autophagy is an intracellular self-digestion mechanism that plays a role in the ER protein quality control process. Unsurprisingly then, basal levels of autophagy were recently found to confer a survival and drugresistance benefit to MM cells. However, excessive induction of autophagy in MM cells leads to autophagic cell death, highlighting the double-edged nature of autophagy modulation in MM. This review provides an overview of the role that autophagy plays in MM pathogenesis, survival, and drug-resistance. We highlight the potential utility of therapeutically targeting autophagy in MM, focusing on preclinical data of autophagic modulators in combination with alkylators, anthracyclines, PI, and immunomodulatory drugs.