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).

In an effort to better understand the molecular underpinnings of PDAC dependence on autophagy, we recently demonstrated that genetic suppression of KRAS, the driver oncogene in PDAC, or pharmacological inhibition of its effector, ERK MAPK, enhances the reliance of PDAC on autophagy. Thus, inhibition of ERK further sensitizes PDAC to autophagy inhibition by HCQ, leading to synergistic decreases in tumour cell proliferation, enhanced apoptosis and decreased tumour growth in vivo (Bryant et al. 2019). Independently, a companion study from the McMahon laboratory demonstrated dramatic antitumour activity of combined HCQ and MEK inhibitors in PDAC and mouse models of other cancers driven by Kras or Braf mutations (Kinsey et al. 2019). These two studies have sanctioned two clinical trials to test the efficacy of combined therapy with MEK inhibitors and HCQ in patients with PDAC; one trial has recently opened (NCT03825289). Thus, the initial description of PDAC addiction to autophagy by the Kimmelman group is now fuelling clinical progress that may lead to effective new treatment options for patients with PDAC.