Dual Inhibition of Autophagy Pathway as a Therapeutic Strategy

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Dual Inhibition of Autophagy Pathway as a Therapeutic Strategy ( dual-inhibition-autophagy-pathway-as-therapeutic-strategy )

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Cancers 2020, 12, 2371 11 of 14 5. Conclusions We showed that HNSCC cell lines that were exposed to PI3Ki displayed increased autophagy and that autophagy inhibitor CQ blocked the PI3Ki-induced autophagy flux. PI3Ki used in conjunction with CQ demonstrated a synergism that enhanced the inhibition of HNSCC cell proliferation and was independent of the PIK3CA status of the cell lines. We present a potential therapeutic strategy of adding CQ to the PI3Ki treatment in HNSCC that is not dependent on the PIK3CA status of the tumor. These results can be translated to in vivo studies and have implications for the design of future clinical trials. Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6694/12/9/2371/s1, Figure S1: PI3K inhibitors and autophagy, Figure S2: Uncropped Western blots. Author Contributions: Conceptualization, M.B. and A.C.; methodology, M.B., F.R.; A.C.; validation, M.B., A.C.; formal analysis, M.B., M.C., G.B.C., D.S., F.R. and A.C.; investigation, M.B., M.C., G.B.C.; writing—original draft preparation, M.B., M.C., G.B.C., D.S., F.R. and A.C.; writing—review and editing, P.F.N.-T., O.B., E.F., H.B., T.A., L.G. and E.B.; visualization, M.B., M.C.; supervision, F.R. and A.C.; project administration, A.C.; funding acquisition, A.C. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the ICM (F.R., A.C.) and by Dr. Azar-Angélil, Chair in Head and Neck Oncology Research of the Université de Montréal to A.C. F.R. and A.C. are researchers of the CRCHUM/ICM, which receive support from the Fonds de Recherche du Québec-Santé (FRQS). F.R. is supported by a FRQS senior award (281706). M.C. received a Canderel fellowships from the ICM. Acknowledgments: The authors thank members of the Mes-Masson, Rodier and Christopoulos laboratories for valuable comments and discussions and Jacqueline Chung for editing. We thank the real-time imaging core facility of the ICM and the cellular imaging core facility of the CRCHUM for imaging and microscopy. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References 1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30. [CrossRef] [PubMed] 2. Pulte, D.; Brenner, H. Changes in survival in head and neck cancers in the late 20th and early 21st century: A period analysis. Oncologist 2010, 15, 994–1001. [CrossRef] [PubMed] 3. Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015, 517, 576–582. [CrossRef] [PubMed] 4. Leemans, C.R.; Snijders, P.J.F.; Brakenhoff, R.H. The molecular landscape of head and neck cancer. Nat. Rev. Cancer 2018, 18, 269–282. [CrossRef] 5. Maira, S.M.; Pecchi, S.; Huang, A.; Burger, M.; Knapp, M.; Sterker, D.; Schnell, C.; Guthy, D.; Nagel, T.; Wiesmann, M.; et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 2012, 11, 317–328. [CrossRef] 6. Knight, S.D.; Adams, N.D.; Burgess, J.L.; Chaudhari, A.M.; Darcy, M.G.; Donatelli, C.A.; Luengo, J.I.; Newlander, K.A.; Parrish, C.A.; Ridgers, L.H.; et al. Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med. Chem. Lett. 2010, 1, 39–43. [CrossRef] 7. Wirtz, E.D.; Hoshino, D.; Maldonado, A.T.; Tyson, D.R.; Weaver, A.M. Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies. JAMA Otolaryngol. Head Neck Surg. 2015, 141, 543–549. [CrossRef] 8. Cai, Y.; Dodhia, S.; Su, G.H. Dysregulations in the PI3K pathway and targeted therapies for head and neck squamous cell carcinoma. Oncotarget 2017, 8, 22203–22217. [CrossRef] 9. Conciatori, F.; Ciuffreda, L.; Bazzichetto, C.; Falcone, I.; Pilotto, S.; Bria, E.; Cognetti, F.; Milella, M. mTOR Cross-Talk in Cancer and Potential for Combination Therapy. Cancers 2018, 10, 23. [CrossRef] 10. Munster, P.; Aggarwal, R.; Hong, D.; Schellens, J.H.; van der Noll, R.; Specht, J.; Witteveen, P.O.; Werner, T.L.; Dees, E.C.; Bergsland, E.; et al. First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies. Clin. Cancer Res. 2016, 22, 1932–1939. [CrossRef]

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