title: Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors.
abstract: The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphoinositide 3-kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the antiapoptosis gene survivin (BIRC5) and the CSC-associated cytokine interleukin-8. RNA interference-mediated or pharmacologic inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors, CSCs can be reduced within HER2(+) tumors, potentially preventing acquired resistance to anti-HER2 therapy.
authors.affiliation: Departments of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Chakrabarty
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bhola
authors.forename: Cammie
authors.initials: C
authors.lastname: Sutton
authors.forename: Ritwik
authors.initials: R
authors.lastname: Ghosh
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Kuba
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D000077022:Survivin; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; D000068878:Trastuzumab; C107489:BIRC5 protein, human; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C508053:ERBB2 protein, human