Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

Qing Bai She; Sofia K. Gruvberger-Saal; Matthew Maurer; Yilun Chen; Mervi Jumppanen; Tao Su; Meaghan Dendy; Ying Ka Ingar Lau; Lorenzo Memeo; Hugo M. Horlings; Marc J. van de Vijver; Jorma Isola; Hanina Hibshoosh; Neal Rosen; Ramon Parsons; Lao H. Saal

doi:10.1186/s12885-016-2609-2

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

Qing Bai She
, Sofia K. Gruvberger-Saal
, Matthew Maurer
, Yilun Chen
, Mervi Jumppanen
, Tao Su
, Meaghan Dendy
, Ying Ka Ingar Lau
, Lorenzo Memeo
, Hugo M. Horlings
, Marc J. van de Vijver
, Jorma Isola
, Hanina Hibshoosh
, Neal Rosen
, Ramon Parsons
, Lao H. Saal

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.

Original language	English
Article number	587
Journal	BMC Cancer
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s12885-016-2609-2
State	Published - Aug 2 2016

Bibliographical note

Publisher Copyright:
© 2016 The Author(s).

Funding

This study was funded by the U.S. National Institutes of Health (Medical Scientist Training Grant 5 T32 GM07367-29 [LHS], R01 CA175105 [Q-BS], P01 CA097403 and R01 CA082783 [RP], P01 CA094060 [NR]), Stand Up To Cancer Dream Team (MM, NR, RP), the Avon Foundation (HH and RP), and the Swedish Cancer Society, Swedish Research Council, Governmental Funding of Clinical Research within National Health Service, Mrs. Berta Kamprad Foundation, Skåne University Hospital Foundation, King Gustav V’s Jubilee Foundation, Krapperup Foundation, Gunnar Nilsson Cancer Foundation, and Crafoord Foundation (all to LHS). The funders had no role in the study design, data gathering, data analysis, data interpretation, decision to publish, or writing of the report.

Funders	Funder number
Krapperup Foundation
National Health Service, Mrs. Berta Kamprad Foundation
National Institutes of Health (NIH)	5 T32 GM07367-29, R01 CA175105, P01 CA094060, P01 CA097403, R01 CA082783
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	T32GM007367
Avon Foundation for Women
Cancerfonden
Crafoordska Stiftelsen
Gunnar Nilssons Cancerstiftelse
Vetenskapsrådet
Stiftelsen Konung Gustaf V:s Jubileumsfond
University of Alberta Hospital Foundation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Basal-like
Breast cancer
Combination therapy
EGFR
PTEN

ASJC Scopus subject areas

Oncology
Genetics
Cancer Research

Access to Document

10.1186/s12885-016-2609-2

Cite this

She, Q. B., Gruvberger-Saal, S. K., Maurer, M., Chen, Y., Jumppanen, M., Su, T., Dendy, M., Lau, Y. K. I., Memeo, L., Horlings, H. M., van de Vijver, M. J., Isola, J., Hibshoosh, H., Rosen, N., Parsons, R., & Saal, L. H. (2016). Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer, 16(1), Article 587. https://doi.org/10.1186/s12885-016-2609-2

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title = "Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer",

abstract = "Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. Results: Sixty-four \% of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 \% of cases had one or more aberration including 97 \% of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.",

keywords = "Basal-like, Breast cancer, Combination therapy, EGFR, PTEN",

author = "She, \{Qing Bai\} and Gruvberger-Saal, \{Sofia K.\} and Matthew Maurer and Yilun Chen and Mervi Jumppanen and Tao Su and Meaghan Dendy and Lau, \{Ying Ka Ingar\} and Lorenzo Memeo and Horlings, \{Hugo M.\} and \{van de Vijver\}, \{Marc J.\} and Jorma Isola and Hanina Hibshoosh and Neal Rosen and Ramon Parsons and Saal, \{Lao H.\}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = aug,

day = "2",

doi = "10.1186/s12885-016-2609-2",

language = "English",

volume = "16",

number = "1",

}

She, QB, Gruvberger-Saal, SK, Maurer, M, Chen, Y, Jumppanen, M, Su, T, Dendy, M, Lau, YKI, Memeo, L, Horlings, HM, van de Vijver, MJ, Isola, J, Hibshoosh, H, Rosen, N, Parsons, R & Saal, LH 2016, 'Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer', BMC Cancer, vol. 16, no. 1, 587. https://doi.org/10.1186/s12885-016-2609-2

TY - JOUR

T1 - Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

AU - She, Qing Bai

AU - Gruvberger-Saal, Sofia K.

AU - Maurer, Matthew

AU - Chen, Yilun

AU - Jumppanen, Mervi

AU - Su, Tao

AU - Dendy, Meaghan

AU - Lau, Ying Ka Ingar

AU - Memeo, Lorenzo

AU - Horlings, Hugo M.

AU - van de Vijver, Marc J.

AU - Isola, Jorma

AU - Hibshoosh, Hanina

AU - Rosen, Neal

AU - Parsons, Ramon

AU - Saal, Lao H.

PY - 2016/8/2

Y1 - 2016/8/2

N2 - Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.

AB - Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.

KW - Basal-like

KW - Breast cancer

KW - Combination therapy

KW - EGFR

KW - PTEN

UR - https://www.scopus.com/pages/publications/84980343511

UR - https://www.scopus.com/pages/publications/84980343511#tab=citedBy

U2 - 10.1186/s12885-016-2609-2

DO - 10.1186/s12885-016-2609-2

M3 - Article

C2 - 27484095

AN - SCOPUS:84980343511

SN - 1471-2407

VL - 16

JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 587

ER -

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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