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Review
. 2023 Jun 23;12(13):1702.
doi: 10.3390/cells12131702.

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

Eloïne Bestion  1 , Eric Raymond  1   2 , Soraya Mezouar  1   3 , Philippe Halfon  1
Affiliations
Review

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

Eloïne Bestion et al. Cells. .

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.

Keywords: PPT1; autophagy; cancer; clinical trial; combinational therapy; drug inhibitor.

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Conflict of interest statement

The authors are employees of Genoscience Pharma.

Figures

Figure 1
Figure 1
The molecular machinery of mammalian canonical autophagy and its pre-clinical and clinical targets. The complex autophagy process can be dissected into seven steps. (1) The induction phase of autophagy is controlled by the Unc-51-like autophagy activating kinase 1 complex (ULK1 complex), composed of ULK1/2 proteins and three other protein partners: the FAK family-interacting protein of 200 kD (FIP200), autophagy-related protein 13 (ATG13), and autophagy-related protein 101 (ATG101), to mediate the mammalian/mechanistic target of rapamycin (mTOR) signals. The ULK1 complex assimilates the stress signal received from mTOR complex 1 (mTORC1), activates it, and is responsible for the initiation of phagophore formation, the unclosed autophagosome structure. Immediately downstream of ULK1 complex activation, the class-III phosphatidylinositol 3-kinase (PI3K-III)/vacuolar protein sorting 34 (VPS34) complex, formed by VPS34 and by regulatory proteins vacuolar sorting protein 15 (VPS15), Beclin1 (BECN1), autophagy and beclin 1 regulator 1 (AMBRA1) and ATG14L, is phosphorylated and activated. This new complex participates in phagophore (2) nucleation and membrane isolation, elongation, and completion. It furthermore controls the conversion of phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PI3P). Local PI3P production occurs at a characteristic ER structure called the omegasome. PI3P then recruits the PI3P effector proteins WD repeat domain phosphoinositide-interacting proteins (WIPI) to the omegasome via interaction with their PI3P-binding domains. (3) Follows the preparation of phagophore membranes for phagophore recruitment to conjugation systems responsible for autophagosome formation. The two ubiquitin-like conjugation systems include the Atg12 conjugation system and the microtubule-associated protein 1A/1B-light chain 3 (LC3) conjugation system, both catalyzed by ATG7. The Atg12 conjugation system forms after ATG12 conjugates to ATG5, both stabilized by the ATG16L protein. The recruitment of the ATG12-ATG5–ATG16L1 complex starts provoking ATG3-mediated conjugation, crucial for the two conjugation systems’ end of execution. In the meantime, the LC3 conjugation machinery has conjugated microtubule-associated protein light chain 3 (LC3) with ATG4 forming LC3-I which is then converted into LC3-II after LC3-I conjugation with membrane-resident phosphatidylethanolamine (PE). The attached-LC3-II to the autophagosome serves as a docking site for the ubiquitin-binding protein (p62) and neighbor of the BRCA1 gene 1 protein (NBR1) that will trap organelles and proteins tagged by ubiquitination for their autophagic degradation. (4) Full execution of the conjugation systems and the presence of associated-LC3-II with PE on the forming autophagosome will participate in its elongation, arching, and closing. Sealing of the phagophore membranes gives rise to a double-layered vesicle called the autophagosome. (5) The autophagosome vesicle then matures before its (6) fusion with the lysosome, forming an autolysosome degradative structure. (7) Acidic lysosomal hydrolases are released nearby the previous embedded cellular components leading to their breakdown into essential products before being discharged and used for the biosynthesis of new components and to fuel cells. Multiple early (ULK and VPS34 inhibitors) and late (V-ATPase and PPT1 inhibitors) pharmacological autophagy blockers are currently under pre-clinical, and for some, clinical evaluation.
Figure 2
Figure 2
Autophagy—a double-edged-word in cancer. Tumorigenesis starts with an oncogene mutation in the healthy tissue that makes cells grow and divide in an uncontrolled fashion, rapidly evolving from the hyperplasia-to-dysplasia stage followed by the in situ cancer stage. The altered cells exhibit changed morphology and behavior while they display an immature phenotype. Tumor cells then invade close-by areas until lymphatic and blood circulating system spread from the primary tumor site to distant sites, forming metastasis. Autophagy’s highly dynamic mechanism is permanently modulated during the tumorigenic process, working for both cancer suppression and promotion.
Figure 3
Figure 3
(A) The main cellular components of the tumor microenvironment (TME) and (B) immune cells’ cross-talk with cancer cells associated with therapeutic strategies. (A) The TME encompasses immune cells, stromal cells, the extracellular matrix (ECM), and blood vessels. It is composed of cancer and heterogeneous non-malignant cells integrated into a complex molecules and matrix network. The relevant cellular components are T cells including cytotoxic T cells (CD8+), tumor-associated macrophages (TAMs), natural killer (NK) cells, cancer-associated fibroblasts (CAFs), dendritic cells (DCs), neutrophils, and monocytes. (B) MHC-I degradation through the autophagy process using the NBR1 cargo protein prevents TCR recognition leading to T cells’ anti-tumoral cytotoxic activity blockade. PPT1 inhibitor use allows for increased MHC-I molecule presentation on cancer cells’ surface, restoring T cells’ killing capacity towards malignant cells. PPT1 inhibitor treatment further leads to TAMs repolarization from the M2 to M1 phenotype, provoking pro-inflammatory secretion that boost NK cells’ and DCs’ infiltration into the tumor site, enabling T cells’ cytotoxic activity and infiltration. M1 abundance achieves cancer cell phagocytosis and killing, while the M2 phenotype’s low presence refrains not only cancer cells’ survival, invasion, and metastasis but increases T cells recruitment as well. PPT1 inhibitor use enhances immune checkpoint blockers’ efficacy, further dampening immune evasion.
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