Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

Cynthia I Chude, Ravi K Amaravadi, Cynthia I Chude, Ravi K Amaravadi

Abstract

Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.

Keywords: Hydroxychloroquine; autophagy; cancer; clinical trials; lysosomes; potent autophagy inhibitors; retinopathy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the autophagic pathway and potential drug target points of the pathway. The autophagic pathway involves the following steps: induction, nucleation, maturation and degradation. Initiation of the pathway begins with growth factors signaling the activation of the mammalian target of rapamycin (mTORC1). The Unc-51-like kinase 1 (ULK1) complex consisting of autophagy-related gene 13 (ATG13) and family interacting protein of 200 Kd ( FIP200) is required to initiate Beclin 1 class III PI3K complex, which is responsible for initiating the Vacuolar Protein Sorting Protein 34 (Vps34), Beclin 1, ATG14L, p150 complex that initiates the formation of the phagophore membrane. ATG12-ATG5 and the microtubule-associated protein light chain 3 (LC3) conjugates are essential for the formation of the autophagosome and its degradation in the lysosome.

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