title: p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
abstract: The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Kuo
authors.affiliation: Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Sharifi
authors.affiliation: Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America; Department of Pathology, University of Chicago, Chicago, Illinois, United States of America; Comprehensive Cancer Center; University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Omar
authors.initials: O
authors.lastname: Ahmed
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Nagilla
authors.affiliation: Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America; Comprehensive Cancer Center; University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Kay F
authors.initials: KF
authors.lastname: Macleod
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States of America; Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America; Comprehensive Cancer Center; University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D013449:Sulfonamides / Q000494:pharmacology; D046888:Tissue Array Analysis; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D000071193:Autophagy-Related Protein 7; D058534:Class I Phosphatidylinositol 3-Kinases; D006575:Heterocyclic Compounds, 3-Ring; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines; D000071456:Sequestosome-1 Protein; D013449:Sulfonamides; D044764:Ubiquitin-Activating Enzymes; C548887:MK 2206; C099718:SQSTM1 protein, human; C581157:XL147; C484760:PIK3CA protein, human; C509349:ATG7 protein, human