title: Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations.
abstract: OBJECTIVE
  ActivatingPIK3CAgenomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC.
  
  
  METHODS
  The efficacy of GDC-0032 was assessedin vitroin 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for γH2AX foci, and cell cycle analysis was performed with flow cytometry.In vivoefficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice.
  
  
  RESULTS
  GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines withPIK3CAmutations or amplification, whereas cell lines withPTENalterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitizedPIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2-M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alonein vivoin subcutaneous xenograft models.
  
  
  CONCLUSIONS
  GDC-0032 has increased potency in HNSCC cell lines harboringPIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone inPIK3CA-altered HNSCCin vitroandin vivo This strategy warrants further clinical investigation.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Zumsteg
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York.
authors.forename: Natasha
authors.initials: N
authors.lastname: Morse
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Krigsfeld
authors.affiliation: Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Gaorav
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Higginson
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York.
authors.forename: Luc
authors.initials: L
authors.lastname: Morris
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York.
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.affiliation: Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Stephan L
authors.initials: SL
authors.lastname: Shiao
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D005784:Gene Amplification; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D010077:Oxazepines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D010077:Oxazepines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; C484760:PIK3CA protein, human