Leaving the Lysosome Behind: Novel Developments in Autophagy Inhibition

Abstract

The search for a single silver bullet for the treatment of cancer has now been overshadowed by the identification of multiple therapeutic targets unique to each malignancy and even to each patient. In recent years, autophagy has emerged as one such therapeutic target. In response to both therapeutic and oncogenic stress, cancer cells upregulate and demonstrate an increased dependence upon this intracellular recycling process. Particularly in malignancies that currently lack targeted therapeutic options, autophagy inhibitors are the next hopeful prospects for the treatment of this disease. In this review, we discuss the rapid evolution of autophagy inhibitors from early lysosomotropic agents to next-generation lysosome-targeted drugs and beyond.

Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

“…The largest limitations to autophagy treatment in clinical trials has been the high doses required of chloroquine, which may fail to achieve intratumoral concentrations sufficient to limit autophagy, and a lack of accepted methodology for monitoring autophagy in patients’ tumors to confirm successful inhibition (53). As such, a large body of research is investigating potential small molecule inhibitors of autophagy, and few have been discovered (54). SAR405 is one such inhibitor that specifically targets PI3K class III, of which the only recognized member is Vps34, an upstream autophagy regulating kinase.…”

TP53INP2 mediates autophagic degradation of ubiquitinated proteins through its ubiquitin‐interacting motif

“…Inhibition of lysosomes and proteasomes has emerged as an effective therapeutic strategy for treating various cancers [24,25]. Inhibition of lysosomes and proteasomes has emerged as an effective therapeutic strategy for treating various cancers [24,25].…”

An overview on the role of autophagy in cancer therapy

“…Also, its combination with a proteasome inhibitor (bortezomib) in relapsed/refractory myeloma patients resulted in a higher rate of partial response and stable disease [30]). More recently, the use of HCQ in combination with gemcitabine in pancreatic ductal adenocarcinoma patients caused significant decreases in the disease biomarker, CA 19-9, with the mean overall survival being extended to nearly 3 years [28,31]. Although clinical trials with these compounds indicate that autophagy inhibition in patients is possible, there is still room for improvement, since CQ/HCQ have also shown significant variability of autophagy inhibition levels among patients.…”

“…Several clinical trials have been evaluating the use of autophagy inhibitors (particularly HCQ) in combination to chemo-and radiotherapy to improve its efficacy [27,28]. A study carried out in melanoma patients using HCQ in combination with the mTOR inhibitor (temsirolimus) showed an improvement of the median progressionfree survival to 3.5 months and increased the rate of stable disease in patients [27,29].…”

“…Although clinical trials with these compounds indicate that autophagy inhibition in patients is possible, there is still room for improvement, since CQ/HCQ have also shown significant variability of autophagy inhibition levels among patients. Moreover, these type of compounds, although being already FDA approved, have to be administered in higher concentrations to inhibit autophagy and are retained for long periods of time in patients (some studies showing patients retaining HCQ) in their system up to 5 years [28,32].…”