Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors

Anindita Chakrabarty, Neil E. Bhola, Cammie Sutton, Ritwik Ghosh, María Gabriela Kuba, Bhuvanesh Dave, Jenny C. Chang, Carlos L. Arteaga

Research output: Contribution to journalArticle

73 Citations (Scopus)

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 trastuzumabresistant 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.

Original languageEnglish (US)
Pages (from-to)1190-1200
Number of pages11
JournalCancer Research
Volume73
Issue number3
DOIs
StatePublished - Feb 1 2013

Fingerprint

1-Phosphatidylinositol 4-Kinase
Neoplastic Stem Cells
Breast Neoplasms
Neoplasms
Therapeutics
Trastuzumab
Antibodies
RNA Interference
Interleukin-8
Drug Resistance
Heterografts
RNA
Apoptosis
Cytokines
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. / Chakrabarty, Anindita; Bhola, Neil E.; Sutton, Cammie; Ghosh, Ritwik; Kuba, María Gabriela; Dave, Bhuvanesh; Chang, Jenny C.; Arteaga, Carlos L.

In: Cancer Research, Vol. 73, No. 3, 01.02.2013, p. 1190-1200.

Research output: Contribution to journalArticle

Chakrabarty, A, Bhola, NE, Sutton, C, Ghosh, R, Kuba, MG, Dave, B, Chang, JC & Arteaga, CL 2013, 'Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors', Cancer Research, vol. 73, no. 3, pp. 1190-1200. https://doi.org/10.1158/0008-5472.CAN-12-2440
Chakrabarty, Anindita ; Bhola, Neil E. ; Sutton, Cammie ; Ghosh, Ritwik ; Kuba, María Gabriela ; Dave, Bhuvanesh ; Chang, Jenny C. ; Arteaga, Carlos L. / Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. In: Cancer Research. 2013 ; Vol. 73, No. 3. pp. 1190-1200.
@article{6aa6a67d7b234c70ade44ae26fa1d8b6,
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 trastuzumabresistant 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.",
author = "Anindita Chakrabarty and Bhola, {Neil E.} and Cammie Sutton and Ritwik Ghosh and Kuba, {Mar{\'i}a Gabriela} and Bhuvanesh Dave and Chang, {Jenny C.} and Arteaga, {Carlos L.}",
year = "2013",
month = "2",
day = "1",
doi = "10.1158/0008-5472.CAN-12-2440",
language = "English (US)",
volume = "73",
pages = "1190--1200",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors

AU - Chakrabarty, Anindita

AU - Bhola, Neil E.

AU - Sutton, Cammie

AU - Ghosh, Ritwik

AU - Kuba, María Gabriela

AU - Dave, Bhuvanesh

AU - Chang, Jenny C.

AU - Arteaga, Carlos L.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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 trastuzumabresistant 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.

AB - 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 trastuzumabresistant 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.

UR - http://www.scopus.com/inward/record.url?scp=84873445750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873445750&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-12-2440

DO - 10.1158/0008-5472.CAN-12-2440

M3 - Article

VL - 73

SP - 1190

EP - 1200

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 3

ER -