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Targeting autophagy in cancer - Nature Reviews Cancer

  • ️Thorburn, Andrew
  • ️Fri Jul 28 2017
  • Klionsky, D. J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937 (2007).

    CAS  PubMed  Google Scholar 

  • The Nobel Assembly. The Nobel Assembly at Karolinska Institutet has today decided to award the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html (2016).

  • Amaravadi, R., Kimmelman, A. C. & White, E. Recent insights into the function of autophagy in cancer. Genes Dev. 30, 1913–1930 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. http://dx.doi.org/10.15252/embj.201490784 (2015).

  • Levy, J. M. & Thorburn, A. Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol. Ther. 131, 130–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007).

    CAS  PubMed  Google Scholar 

  • Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011). A detailed discussion of the protein and membrane interactions required for autophagosome formation.

    CAS  PubMed  Google Scholar 

  • Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999). Beclin 1 is identified as a putative tumour suppressor.

    CAS  PubMed  Google Scholar 

  • Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1–222 (2016). The definitive consensus of experimental methods that are appropriate for the study of autophagy.

    PubMed  PubMed Central  Google Scholar 

  • Bago, R. et al. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413–427 (2014).

    CAS  PubMed  Google Scholar 

  • Dowdle, W. E. et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell Biol. 16, 1069–1079 (2014).

    CAS  PubMed  Google Scholar 

  • Ronan, B. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10, 1013–1019 (2014).

    CAS  PubMed  Google Scholar 

  • Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Petherick, K. J. et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J. Biol. Chem. 290, 11376–11383 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akin, D. et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10, 2021–2035 (2014).

    PubMed  PubMed Central  Google Scholar 

  • McAfee, Q. et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc. Natl Acad. Sci. USA 109, 8253–8258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goodall, M. L. et al. Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib. Autophagy 10, 1120–1136 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Malik, S. A. et al. BH3 mimetics activate multiple pro-autophagic pathways. Oncogene 30, 3918–3929 (2011).

    CAS  PubMed  Google Scholar 

  • Nazio, F. et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 15, 406–416 (2013).

    CAS  PubMed  Google Scholar 

  • DeBosch, B. J. et al. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci. Signal. 9, ra21 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Marino, G., Pietrocola, F., Madeo, F. & Kroemer, G. Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Autophagy 10, 1879–1882 (2014).

    PubMed  PubMed Central  Google Scholar 

  • He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li, W. W., Li, J. & Bao, J. K. Microautophagy: lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125–1136 (2012).

    CAS  PubMed  Google Scholar 

  • Arias, E. & Cuervo, A. M. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184–189 (2011).

    CAS  PubMed  Google Scholar 

  • Kaushik, S. et al. Chaperone-mediated autophagy at a glance. J. Cell Sci. 124, 495–499 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kon, M. et al. Chaperone-mediated autophagy is required for tumor growth. Sci. Transl Med. 3, 109ra117 (2011).

    PubMed  PubMed Central  Google Scholar 

  • Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007). Therapy with autophagy inhibition is identified as having combinatory effects with other anticancer agents.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thorburn, A., Thamm, D. H. & Gustafson, D. L. Autophagy and cancer therapy. Mol. Pharmacol. 85, 830–838 (2014).

    PubMed  PubMed Central  Google Scholar 

  • Yang, Y. P. et al. Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol. Sin. 34, 625–635 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maycotte, P. et al. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy 8, 200–212 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eng, C. H. et al. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc. Natl Acad. Sci. USA 113, 182–187 (2016).

    CAS  PubMed  Google Scholar 

  • Maes, H. et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26, 190–206 (2014).

    CAS  PubMed  Google Scholar 

  • Briceno, E., Reyes, S. & Sotelo, J. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg. Focus 14, e3 (2003). The results of the first clinical trial to evaluate the antitumour effects of CQ, which showed improved clinical outcomes with autophagy inhibition in glioblastoma.

    PubMed  Google Scholar 

  • Briceno, E., Calderon, A. & Sotelo, J. Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg. Neurol. 67, 388–391 (2007).

    PubMed  Google Scholar 

  • Sotelo, J., Briceno, E. & Lopez-Gonzalez, M. A. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 144, 337–343 (2006).

    CAS  PubMed  Google Scholar 

  • Eldredge, H. B. et al. Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial. J. Radiat. Oncol. 2, 315–321 (2013).

    CAS  Google Scholar 

  • Rojas-Puentes, L. L. et al. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat. Oncol. 8, 209 (2013).

    PubMed  PubMed Central  Google Scholar 

  • Barnard, R. A. et al. Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 10, 1415–1425 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mahalingam, D. et al. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 10, 1403–1414 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rangwala, R. et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391–1402 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rangwala, R. et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10, 1369–1379 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenfeld, M. R. et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 10, 1359–1368 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vogl, D. T. et al. Combined autophagy and proteasome inhibition: A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 10, 1380–1390 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wolpin, B. M. et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637–638 (2014).

    PubMed  PubMed Central  Google Scholar 

  • Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014). An evaluation of the genetic knockout of autophagy-related genes and the growth of tumour cells in vivo , and the identification of a therapeutic window to inhibit autophagy in lung cancer growth and development.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pellegrini, P. et al. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. Autophagy 10, 562–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, T. et al. Synthesis of improved lysomotropic autophagy inhibitors. J. Med. Chem. 58, 3025–3035 (2015).

    CAS  PubMed  Google Scholar 

  • Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boone, B. A. et al. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Ann. Surg. Oncol. 22, 4402–4410 (2015).

    PubMed  PubMed Central  Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01881451?term=NCT01881451&rank=1(2016).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02233387?term=NCT02233387&rank=1(2016).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01206530?term=NCT01206530&rank=1 (2017).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02042989?term=NCT02042989&rank=1(2017).

  • Fullgrabe, J., Heldring, N., Hermanson, O. & Joseph, B. Cracking the survival code: autophagy-related histone modifications. Autophagy 10, 556–561 (2014).

    PubMed  PubMed Central  Google Scholar 

  • Wang, H. et al. Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis. Sci. Rep. 6, 26456 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perera, R. M. et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Follo, C., Barbone, D., Richards, W. G., Bueno, R. & Broaddus, V. C. Autophagy initiation correlates with the autophagic flux in 3D models of mesothelioma and with patient outcome. Autophagy 12, 1180–1194 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lock, R., Kenific, C. M., Leidal, A. M., Salas, E. & Debnath, J. Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. Cancer Discov. 4, 466–479 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kraya, A. A. et al. Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy 11, 60–74 (2015).

    PubMed  Google Scholar 

  • Maycotte, P., Jones, K. L., Goodall, M. L., Thorburn, J. & Thorburn, A. Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Mol. Cancer Res. 4, 651–658 (2015).

    Google Scholar 

  • Varadarajulu, S. & Bang, J. Y. Role of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in the clinical assessment of pancreatic neoplasms. Surg. Oncol. Clin. N. Am. 25, 255–272 (2016).

    PubMed  Google Scholar 

  • Feng, Y., He, D., Yao, Z. & Klionsky, D. J. The machinery of macroautophagy. Cell Res. 24, 24–41 (2014). Basic review of the history and core machinery involved in the process of autophagy.

    CAS  PubMed  Google Scholar 

  • Altman, J. K. et al. Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting. Clin. Cancer Res. 20, 2400–2409 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kun, Z. et al. Gastrin enhances autophagy and promotes gastric carcinoma proliferation via inducing AMPKα. Oncol. Res. http://dx.doi.org/10.3727/096504016X14823648620870 (2017).

  • Masui, A. et al. Autophagy as a survival mechanism for squamous cell carcinoma cells in endonuclease G-mediated apoptosis. PLoS ONE 11, e0162786 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Tan, Q. et al. Role of autophagy as a survival mechanism for hypoxic cells in tumors. Neoplasia 18, 347–355 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fitzwalter, B. E. & Thorburn, A. Recent insights into cell death and autophagy. FEBS J. 282, 4279–4288 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gump, J. M. et al. Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat. Cell Biol. 16, 47–54 (2014).

    CAS  PubMed  Google Scholar 

  • Thorburn, J. et al. Autophagy controls the kinetics and extent of mitochondrial apoptosis by regulating PUMA levels. Cell Rep. 7, 45–52 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goodall, M. L. et al. The autophagy machinery controls cell death switching between apoptosis and necroptosis. Dev. Cell 37, 337–349 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rao, S., Yang, H., Penninger, J. M. & Kroemer, G. Autophagy in non-small cell lung carcinogenesis: a positive regulator of antitumor immunosurveillance. Autophagy 10, 529–531 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, Y., Galluzzi, L., Zitvogel, L. & Kroemer, G. Autophagy and cellular immune responses. Immunity 39, 211–227 (2013).

    CAS  PubMed  Google Scholar 

  • Townsend, K. N. et al. Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity. Immunol. Rev. 249, 176–194 (2012).

    CAS  PubMed  Google Scholar 

  • Ko, A. et al. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ. 21, 92–99 (2014).

    CAS  PubMed  Google Scholar 

  • Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    CAS  PubMed  Google Scholar 

  • Lechner, M. G. et al. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy. J. Immunother. 36, 477–489 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Starobinets, H. et al. Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment. J. Clin. Invest. 126, 4417–4429 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Y. et al. The vitamin E analogue α-TEA stimulates tumor autophagy and enhances antigen cross-presentation. Cancer Res. 72, 3535–3545 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ladoire, S. et al. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy 11, 1878–1890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ladoire, S. et al. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer. Autophagy 12, 864–875 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Baginska, J. et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl Acad. Sci. USA 110, 17450–17455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liang, X. et al. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Res. 72, 2791–2801 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03057340?term=NCT03057340&rank=1 (2017).

  • Page, D. B. et al. Glimpse into the future: harnessing autophagy to promote anti-tumor immunity with the DRibbles vaccine. J. Immunother. Cancer 4, 25 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Yu, G. L. et al. Combinational immunotherapy with allo-DRibble vacciens and anti-OX40 co-stimulation leads to generation of cross-reactive effector T cells and tumor regression. Sci. Rep. 6, http://dx.doi.org/10.1038/srep37558 (2016).

  • Hilton, T. S. et al. Preliminary analysis of immune responses in patients enrolled in a Phase II trial of cyclophosphamide wiht allogenic DRibble vaccine alone (DPV-001) or with GM-CSF or imiquimod for adjuvant treatment of stage IIIA or IIIB NSCLC. J. Immunother. Cancer 2, 249 (2014).

    Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01956734?term=NCT01956734&rank=1 (2015).

  • Levy, J. M. M. et al. Autophagy inhibition improves chemosensitivity in BRAFV600E brain tumors. Cancer Discov. 4, 773–780 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maycotte, P. et al. STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious. Cancer Res. 74, 2579–2590 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lock, R. et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22, 165–178 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).

    CAS  PubMed  Google Scholar 

  • Xie, X., Koh, J. Y., Price, S., White, E. & Mehnert, J. M. Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma. Cancer Discov. 5, 410–423 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mancias, J. D. & Kimmelman, A. C. Targeting autophagy addiction in cancer. Oncotarget 2, 1302–1306 (2011).

    PubMed  PubMed Central  Google Scholar 

  • Thorburn, A. & Morgan, M. J. Targeting autophagy in BRAF-mutant tumors. Cancer Discov. 5, 353–354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Levine, B. & Abrams, J. p53: the Janus of autophagy? Nat. Cell Biol. 10, 637–639 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang, J. Di, J., Cao, H., Bai, J. & Zheng, J. p53-mediated autophagic regulation: a prospective strategy for cancer therapy. Cancer Lett. 363, 101–107 (2015).

    CAS  PubMed  Google Scholar 

  • Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).

    CAS  PubMed  Google Scholar 

  • Iacobuzio-Donahue, C. A. & Herman, J. M. Autophagy, p53, and pancreatic cancer. N. Engl. J. Med. 370, 1352–1353 (2014).

    CAS  PubMed  Google Scholar 

  • Huo, Y. et al. Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discov. 3, 894–907 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan, M. J. et al. Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent. Autophagy 10, 1814–1826 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vasilevskaya, I. A., Selvakumaran, M., Roberts, D. & O'Dwyer, P. J. JNK1 inhibition attenuates hypoxia-induced autophagy and sensitizes to chemotherapy. Mol. Cancer Res. 14, 753–763 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jutten, B. & Rouschop, K. M. EGFR signaling and autophagy dependence for growth, survival, and therapy resistance. Cell Cycle 13, 42–51 (2014).

    CAS  PubMed  Google Scholar 

  • Guo, D. et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc. Natl Acad. Sci. USA 106, 12932–12937 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jutten, B. et al. EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival. Radiother. Oncol. 108, 479–483 (2013).

    CAS  PubMed  Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02257424?term=NCT02257424&rank=1 (2016).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02378532?term=NCT02378532&rank=1 (2016).

  • Ma, X.-H. et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J. Clin. Invest. 124, 1406–1417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mulcahy Levy, J. M. et al. Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. eLife 6, e19671 (2017). The first demonstration of the use of autophagy inhibition to overcome kinase inhibitor resistance in patients.

    PubMed  PubMed Central  Google Scholar 

  • Kang, M. et al. Concurrent autophagy inhibition overcomes the resistance of epidermal growth factor receptor tyrosine kinase inhibitors in human bladder cancer cells. Int. J. Mol. Sci. 18, 321 (2017).

    PubMed Central  Google Scholar 

  • Wang, W. et al. Targeting autophagy sensitizes BRAF-mutant thyroid cancer to vemurafenib. J. Clin. Endocrinol. Metab. 102, 634–643 (2016).

    PubMed Central  Google Scholar 

  • Liu, J. T. et al. Autophagy inhibition overcomes the antagonistic effect between gefitinib and cisplatin in epidermal growth factor receptor mutant non–small-cell lung cancer cells. Clin. Lung Cancer 16, e55–e66 (2015).

    CAS  PubMed  Google Scholar 

  • Zou, Y. et al. The autophagy inhibitor chloroquine overcomes the innate resistance of wild-type EGFR non-small-cell lung cancer cells to erlotinib. J. Thorac Oncol. 8, 693–702 (2013).

    CAS  PubMed  Google Scholar 

  • Ji, C. et al. Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. Cancer Biol. Ther. 15, 570–577 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, S. F. et al. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer. Autophagy 11, 225–238 (2015).

    PubMed  PubMed Central  Google Scholar 

  • Wang, J. & Wu, G. S. Role of autophagy in cisplatin resistance in ovarian cancer cells. J. Biol. Chem. 289, 17163–17173 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, L. et al. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance. Cancer Lett. 355, 34–45 (2014).

    CAS  PubMed  Google Scholar 

  • Wu, H. M., Jiang, Z. F., Ding, P. S., Shao, L. J. & Liu, R. Y. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci. Rep. 5, 12291 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mahoney, E. et al. ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood 120, 1262–1273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Z. Y. et al. A novel HDAC6 inhibitor Tubastatin A: controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells. Cancer Lett. 391, 89–99 (2017).

    CAS  PubMed  Google Scholar 

  • Aveic, S. & Tonini, G. P. Resistance to receptor tyrosine kinase inhibitors in solid tumors: can we improve the cancer fighting strategy by blocking autophagy? Cancer Cell. Int. 16, 62 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Chen, S. et al. Autophagy is a therapeutic target in anticancer drug resistance. Biochim. Biophys. Acta 1806, 220–229 (2010).

    CAS  PubMed  Google Scholar 

  • Kumar, A., Singh, U. K. & Chaudhary, A. Targeting autophagy to overcome drug resistance in cancer therapy. Future Med. Chem. 7, 1535–1542 (2015).

    CAS  PubMed  Google Scholar 

  • Sannigrahi, M. K., Singh, V., Sharma, R., Panda, N. K. & Khullar, M. Role of autophagy in head and neck cancer and therapeutic resistance. Oral Dis. 21, 283–291 (2015).

    CAS  PubMed  Google Scholar 

  • Sui, X. et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Katheder, N. S. et al. Microenvironmental autophagy promotes tumour growth. Nature 541, 417–420 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pasquier, B. Autophagy inhibitors. Cell. Mol. Life Sci. 73, 985–1001 (2016).

    CAS  PubMed  Google Scholar 

  • Basit, F., Cristofanon, S. & Fulda, S. Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. Cell Death Differ. 20, 1161–1173 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, H. Y. & White, E. Role of autophagy in cancer prevention. Cancer Prev. Res. (Phila.) 4, 973–983 (2011).

    CAS  Google Scholar 

  • Bedoya, V. Effect of chloroquine on malignant lymphoreticular and pigmented cells in vitro. Cancer Res. 30, 1262–1275 (1970). The anti-malarial drug CQ is first shown to inhibit tumour cell growth in vitro , as indicated by the accumulation of autophagic vacuoles.

    CAS  PubMed  Google Scholar 

  • Funakoshi, T., Matsuura, A., Noda, T. & Ohsumi, Y. Analyses of APG13 gene involved in autophagy in yeast, Saccharomyces cerevisiae. Gene 192, 207–213 (1997). The Ohsumi group cloned the first autophagy- specific gene, Apg13 in yeast ( ATG1 in humans).

    CAS  PubMed  Google Scholar 

  • Matsuura, A., Tsukada, M., Wada, Y. & Ohsumi, Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192, 245–250 (1997). The Ohsumi group demonstrated the direct involvement of protein phosphorylation in the regulation of autophagy.

    CAS  PubMed  Google Scholar 

  • Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273, 33889–33892 (1998). The first autophagy-specific genes in higher eukaryotes were identified.

    CAS  PubMed  Google Scholar 

  • Murakami, N. et al. Accumulation of tau in autophagic vacuoles in chloroquine myopathy. J. Neuropathol. Exp. Neurol. 57, 664–673 (1998). The first study to observe that CQ can inhibit autophagy and the connection between the accumulation of cellular proteins and the inhibition of lysosomal degradation.

    CAS  PubMed  Google Scholar 

  • Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004). The first autophagy-deficient mouse ( Atg5−/−) was created, and indicated that autophagy is important during development.

    CAS  PubMed  Google Scholar 

  • Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014). In vivo model that demonstrated the ability of autophagy to repress early oncogenesis but to support late-stage cancer growth.

    PubMed  Google Scholar 

  • Chi, K. H. et al. Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort. Oncotarget 6, 16735–16745 (2015).

    PubMed  PubMed Central  Google Scholar 

  • Chi, M. S. et al. Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients. Oncotarget 6, 29808–29817 (2015).

    PubMed  PubMed Central  Google Scholar 

  • Bilger, A. et al. FET-PET-based reirradiation and chloroquine in patients with recurrent glioblastoma: first tolerability and feasibility results. Strahlenther. Onkol. 190, 957–961 (2014).

    PubMed  Google Scholar 

  • Goldberg, S. B. et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J. Thorac Oncol. 7, 1602–1608 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01594242?term=NCT01594242&rank=1 (2016).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01874548?term=NCT01874548&rank=1 (2016).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01506973?term=NCT01506973&rank=1(2017).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01978184?term=NCT01978184&rank=1 (2015).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01128296?term=NCT01128296&rank=1 (2015).

  • US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01897116?term=NCT01897116&rank=1 (2016).