title: Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer.
abstract: The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is frequently disrupted in cancer and implicated in multiple aspects of tumor growth and survival. In addition, increased activity of this pathway in cancer is associated with resistance to chemotherapeutic agents. Therefore, it has been hypothesized that PI3K inhibitors could help to overcome resistance to chemotherapies. We used preclinical cancer models to determine the effects of combining the DNA-damaging drug doxorubicin with GDC-0941, a class I PI3K inhibitor that is currently being tested in early-stage clinical trials. We found that PI3K inhibition significantly increased apoptosis and enhanced the antitumor effects of doxorubicin in a defined set of breast and ovarian cancer models. Doxorubicin treatment caused an increase in the amount of nuclear phospho-Akt(Ser473) in cancer cells that rely on the PI3K pathway for survival. This increased phospho-Akt(Ser473) response to doxorubicin correlates with the strength of GDC-0941's effect to augment doxorubicin action. These studies predict that clinical use of combination therapies with GDC-0941 in addition to DNA-damaging agents will be effective in tumors that rely on the PI3K pathway for survival.
authors.affiliation: Cancer Signaling, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. jwallin@gene.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Jane
authors.initials: J
authors.lastname: Guan
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Edgar
authors.forename: Robert
authors.initials: R
authors.lastname: Kassees
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000378:metabolism*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000903:Antibiotics, Antineoplastic; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt