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Blocking autophagy to starve pancreatic cancer

Nature Reviews Molecular Cell Biology volume 20, page 265 (2019)Cite this article

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Autophagy — a term derived from the Greek words ‘auto’, meaning ‘self’, and ‘phagein’, meaning ‘to eat’ — is a biological process of literal cellular ‘self-eating’, which enables cells to degrade and recycle cellular components and allows for survival under stress conditions. Although the essentiality of autophagy in cell biology is well established, underscored by the 2016 Nobel Prize in Physiology or Medicine awarded to Yoshinori Ohsumi “for his discovery of the mechanisms for autophagy,” many of the molecular details that underlie autophagy are still unknown. Deregulation of autophagy has been associated with various disease states, including cancer and neurological disorders. Notably, in cancer, autophagy seems to have contrasting, context-dependent roles, either restricting tumour initiation or promoting cancer growth.

The work on autophagy in pancreatic ductal adenocarcinoma (PDAC), spearheaded by the Kimmelman laboratory, indicates that autophagy sustains the growth of this cancer and can be explored as a potential therapeutic target for PDAC. In 2011, the Kimmelman group showed that PDAC cells display high basal levels of autophagic flux. Furthermore, they demonstrated that genetic depletion of autophagic machinery components, or chloroquine-mediated pharmacological inhibition of autophagy, suppressed proliferation of PDAC cells in vitro and decreased tumorigenicity in vivo (Yang et al. 2011). In 2014, they extended this study by completing a mouse preclinical trial, which demonstrated antitumour effects of a chloroquine derivative, hydroxychloroquine (HCQ), in a large panel of patient-derived xenografts (Yang et al. 2014). These studies led to multiple clinical trials with HCQ in patients with PDAC. However, HCQ has shown limited activity as a monotherapy. Recent noteworthy success in this area includes improved surgical outcomes following the use of HCQ in combination with gemcitabine and nab-paclitaxel in preoperative treatment of PDAC patients (NCT01978184).

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Further reading

  • Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018)

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  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kirsten L. Bryant & Channing J. Der

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  1. Kirsten L. Bryant
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  2. Channing J. Der
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Correspondence to Channing J. Der.

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Bryant, K.L., Der, C.J. Blocking autophagy to starve pancreatic cancer. Nat Rev Mol Cell Biol 20, 265 (2019). https://doi.org/10.1038/s41580-019-0120-8

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