Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors

Abstract

Autophagy is a highly conserved and natural degradation process that helps maintain cell homeostasis through the elimination of old, worn, and defective cellular components, ensuring proper cell energy intake. The degradative pathway constitutes a protective barrier against diverse human diseases including cancer. Autophagy basal level has been reported to be completely dysregulated during the entire oncogenic process. Autophagy influences not only cancer initiation, development, and maintenance but also regulates cancer response to therapy. Currently, autophagy inhibitor candidates mainly target the early autophagy process without any successful preclinical/clinical development. Lessons learned from autophagy pharmaceutical manipulation as a curative option progressively help to improve drug design and to encounter new targets of interest. Combinatorial strategies with autophagy modulators are supported by abundant evidence, especially dealing with immune checkpoint inhibitors, for which encouraging preclinical results have been recently published. GNS561, a PPT1 inhibitor, is a promising autophagy modulator as it has started a phase 2 clinical trial in liver cancer indication, combined with atezolizumab and bevacizumab, an assessment without precedent in the field. This approach paves a new road, leading to the resurgence of anticancer autophagy inhibitors as an attractive therapeutic target in cancer.

A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines

“…However, cardiomyocyte autophagy dysfunction is closely associated with the development of arrhythmias ( Luan et al, 2021 ). Autophagy, as a regulatory mechanism, is highly conserved throughout the life cycle of yeast and humans ( Bestion et al, 2023 ), and plays a large role in tumorigenesis ( Amaravadi et al, 2016 ; Udristioiu and Nica-Badea, 2019 ; Zhang et al, 2023 ). Anthracycline-induced myocardial damage is closely related to autophagy ( Koleini and Kardami, 2017 ).…”

Advances of Protein Palmitoylation in Tumor Cell Deaths

“…In the dynamic field of oncology, the therapeutic value of PPT1 inhibitors, such as GNS561 and dimeric chloroquine (DC661), is being recognized [95,96]. DC661 surpasses hydroxychloroquine in inhibiting autophagy by targeting PPT1, while GNS561 shows potential synergy with immune checkpoint inhibitors, marking a shift in cancer treatment strategies [68,97]. Furthermore, the Phase 1b trial of GNS561 reveals its unique mechanism involving lysosomal Zn(2+) accumulation, underlining its therapeutic promise [98].…”