Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

Abstract

Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.

Targeting autophagy in pancreatic cancer: The cancer stem cell perspective

“…The destruction of CSC niches is essential in order to achieve PDAC therapy and avoid cancer recurrence, however CSC niches in PDAC tumors are protected by the low-oxygen tumor environment and this is a major contributing factor to anticancer therapy resistance (29). Possible treatments could arise from the targeting of autophagy in PaCSCs and several preclinical studies are exploring the possibility of eliminating PaCSC niches In addition to the pre-clinical studies, efforts to effectively tackle PDAC currently explore the clinical use of small molecules that target autophagy, in combination with chemotherapy and/or immunotherapy (14). Targeting cancer stemness is currently the basis of ongoing clinical trials on Phase III with paclitaxel/nab paclitaxel and gemcitabine with the addition of napabucasin, a small molecule that inhibits STAT3-mediated gene transcription.…”

“…In addition to the pre-clinical studies, efforts to effectively tackle PDAC currently explore the clinical use of small molecules that target autophagy, in combination with chemotherapy and/or immunotherapy ( 14 ). Targeting cancer stemness is currently the basis of ongoing clinical trials on Phase III with paclitaxel/nab paclitaxel and gemcitabine with the addition of napabucasin, a small molecule that inhibits STAT3-mediated gene transcription.…”

“…Increased autophagic activity in PDAC has long been recognized as a major contributing factor in tumor survival, progression and metastasis. Through autophagy, PDAC tumors gain vital resources for the maintenance of their integrity, and this is achieved via mechanisms that have been expertly reviewed in great detail elsewhere (more recently by Gillson et al, 2022) ( 14 ). Our intention here is to focus on the seemingly contradictory and often debated dual (positive and negative) role of autophagy in PDAC.…”

“…A major cellular process that was found to be critically altered during PDAC initiation and progression is autophagy ( 14 ). Autophagy is a highly conserved “self-digestion” process that involves the catabolism of dysfunctional compounds, damaged organelles and engulfed pathogens to maintain cellular integrity and survival.…”

The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches

“…The above phenomenon is implied by the fact that mice who lack autophagy mechanisms and present KRAS mutation have an increased risk of developing PanIN, which constitutes a precursor of PDAC [ 67 ]. Last but not least, the autophagy pathway also presents the role metastasis suppressor by inhibiting tissue transglutaminase (TG2) which is implicated in metastatic dissemination [ 68 ].…”