Targeting Autophagy in Cancer: Recent Advances and Future Directions
Top Cited Papers
- 20 August 2019
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 9 (9), 1167-1181
- https://doi.org/10.1158/2159-8290.CD-19-0292
Abstract
Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specific autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Significance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor micro-environment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefit from this approach.Keywords
Funding Information
- NCI (P01CA114046, P30 CA016520, SPORE P50 CA174523, 1R01CA198015, R01CA157490, R01CA188048, P01CA117969, R35CA232124)
- NIH (R01GM095567)
- Lustgarten Foundation (R01CA201849, R01CA126792, R01CA213775)
This publication has 155 references indexed in Scilit:
- Macropinocytosis of protein is an amino acid supply route in Ras-transformed cellsNature, 2013
- Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1Cell, 2012
- Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiencyProceedings of the National Academy of Sciences of the United States of America, 2012
- Involvement of Autophagy in Oncogenic K-Ras-induced Malignant Cell TransformationPublished by Elsevier BV ,2011
- AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1Nature, 2011
- Plasma membrane contributes to the formation of pre-autophagosomal structuresNature, 2010
- Network organization of the human autophagy systemNature, 2010
- The Selective Macroautophagic Degradation of Aggregated Proteins Requires the PI3P-Binding Protein AlfyMolecular Cell, 2010
- Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino AcidsCell, 2010
- JNK1-Mediated Phosphorylation of Bcl-2 Regulates Starvation-Induced AutophagyMolecular Cell, 2008