title: Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068.
abstract: OBJECTIVE
  The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound.
  
  
  METHODS
  We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial.
  
  
  RESULTS
  The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations.
  
  
  CONCLUSIONS
  This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations.
authors.affiliation: Authors' Affiliations: Oncology Biomarker Development, Portfolio Management and Operations, Translational Oncology, Biostatistics, and Exploratory Clinical Development, Genentech Inc., DNA Way, South San Francisco, California; Experimental Therapeutics, Molecular Pathology, Breast Cancer and Melanoma, Gastrointestinal and Endocrine Tumors Groups, and Medical Oncology Service, Vall d'Hebron Institute of Oncology, Barcelona; Department of Hematology and Medical Oncology, Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain; and Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: Sumati
authors.initials: S
authors.lastname: Murli
authors.forename: Olga
authors.initials: O
authors.lastname: Rodríguez
authors.forename: Marta
authors.initials: M
authors.lastname: Guzman
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Wagle
authors.forename: Jenny Q
authors.initials: JQ
authors.lastname: Wu
authors.forename: Matthew
authors.initials: M
authors.lastname: Wongchenko
authors.forename: Garret
authors.initials: G
authors.lastname: Hampton
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.forename: Cristina
authors.initials: C
authors.lastname: Saura
authors.forename: Desamparados
authors.initials: D
authors.lastname: Roda
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Premal
authors.initials: P
authors.lastname: Patel
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C583616:ipatasertib; C546842:MTOR protein, human