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 Article Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma Monique Bernard 1,2, Guillaume B. Cardin 1,2, Maxime Cahuzac 1,2 , Tareck Ayad 1,3, Eric Bissada 3, Louis Guertin 3, Houda Bahig 1,4, Phuc Felix Nguyen-Tan 4, Edith Filion 4, Olivier Ballivy 4, Denis Soulieres 5 , Francis Rodier 1,2,6 and Apostolos Christopoulos 1,2,3,* 1 2 3 4 5 6 * Correspondence: a.christopoulos@umontreal.ca; Tel.: +514-890-8000 (ext. 31292) Received: 24 July 2020; Accepted: 19 August 2020; Published: 21 August 2020 Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada; monique.bernard.chum@ssss.gouv.qc.ca (M.B.); cardinguill@gmail.com (G.B.C.); maxime.cahuzac@umontreal.ca (M.C.); ayad_t@hotmail.com (T.A.); houda.bahig.chum@ssss.gouv.qc.ca (H.B.); rodierf@mac.com (F.R.) Institut du Cancer de Montréal (ICM), Montreal, QC H2X 0A9, Canada Otolaryngology-Head and Neck Surgery Service, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada; ericbissada@yahoo.com (E.B.); guertinorl@gmail.com (L.G.) Department of Radiation Oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada; felixnguyentan@gmail.com (P.F.N.-T.); edith.filion@gmail.com (E.F.); olivier.ballivy.chum@ssss.gouv.qc.ca (O.B.) Department of Medicine, Service of Hemato-Oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada; denis.soulieres@umontreal.ca Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada Abstract: Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies. Keywords: autophagy; buparlisib; cancer; combination therapy; chloroquine; HNSCC; omipalisib; oral tongue; PI3K inhibitor; PI3K signaling pathway 1. Introduction Head and neck squamous cell carcinoma (HNSCC) is the seventh most common solid cancer in the USA and the five-year relative survival rate is 66% [1,2]. Platinum-based chemotherapy 􏰁􏰂􏰃 􏰅􏰆􏰇 􏰈􏰉􏰊􏰋􏰌􏰂􏰍 Cancers 2020, 12, 2371; doi:10.3390/cancers12092371 www.mdpi.com/journal/cancers

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