title: A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.
abstract: mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy.
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Iglesias-Bartolomé
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Callejas-Valera
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Panomwat
authors.initials: P
authors.lastname: Amornphimoltham
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Ezra E
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (CCR-NCI), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.|Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: co-targeting therapy; rapamycin; shRNA library; synthetic lethality screen; trametinib