title: What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway.
abstract: The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors.
  
  
  CONCLUSIONS
  There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer.
authors.affiliation: 1Division of Hematology-Oncology, University of California Irvine Medical Center, Orange, California; 2Division of Signal Transduction, Beth Israel Deaconess Medical Center; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 4Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Myers
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors