title: Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation.
abstract: PI3K/AKT/mTOR pathway is an established oncogenic driver in humans. Targeted biologic agents against components of this pathway have shown promising activity leading to the approval of the allosteric inhibitors of mTOR, everolimus, and temsirolimus for the treatment of advanced cancers of the kidney, breast, and pancreas. Despite the established and promising activity of this therapeutic strategy, the duration and quality of benefit remains suboptimal in unselected patients. Improved understanding of the biologic consequence of altered PI3K/AKT/mTOR signaling is informing the development of protein (phosphorylated forms of S6, AKT, eIF4e) and genetic (PIK3CA mutation, PTEN loss of function, TSC1 and TSC2 mutation, PIK3CA-GS genetic profile) biomarkers to identify patients most likely to benefit from this therapeutic strategy. This review provides an overview of the biologic rational and promising results of protein and genetic biomarkers for selecting patients appropriate for therapy with inhibitors of this pathway.
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018579:Patient Selection; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases