Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy

被引：22

作者：

Creedon, Helen ^{[1
]}

Gomez-Cuadrado, Laura ^{[1
]}

Tarnauskaite, Zygimante ^{[1
]}

Balla, Jozef ^{[1
]}

Canel, Marta ^{[1
]}

MacLeod, Kenneth G. ^{[1
]}

Serrels, Bryan ^{[1
]}

Fraser, Craig ^{[1
]}

Unciti-Broceta, Asier ^{[1
]}

Tracey, Natasha ^{[1
]}

Le Bihan, Thierry ^{[2
]}

Klinowska, Teresa ^{[3
]}

Sims, Andrew H. ^{[1
]}

Byron, Adam ^{[1
]}

Brunton, Valerie G. ^{[1
]}

机构：

[1] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh Canc Res Ctr, Edinburgh EH4 2XR, Midlothian, Scotland

[2] Univ Edinburgh, SynthSys, Edinburgh EH9 3BF, Midlothian, Scotland

[3] AstraZeneca Oncol iMed, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

来源：

ONCOTARGET | 2016年 / 7卷 / 10期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

resistance; breast cancer; EMT; HER2; proteomics; GROWTH-FACTOR RECEPTOR; TRASTUZUMAB RESISTANCE; ACQUIRED-RESISTANCE; DRUG-RESISTANCE; STEM-CELLS; CANCER; ACTIVATION; EXPRESSION; HER2; COMBINATIONS;

D O I：

10.18632/oncotarget.7317

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in the treatment of HER2-positive breast cancer is a major clinical problem. To identify pathways linked to resistance, we generated HER2-positive breast cancer cell lines which are resistant to either lapatinib or AZD8931, two pan-HER family kinase inhibitors. Resistance was HER2 independent and was associated with epithelial-to-mesenchymal transition (EMT), resulting in increased proliferation and migration of the resistant cells. Using a global proteomics approach, we identified a novel set of EMT-associated proteins linked to HER2-independent resistance. We demonstrate that a subset of these EMT-associated genes is predictive of prognosis within the ERBB2 subtype of human breast cancers. Furthermore, targeting the EMT-associated kinases Src and Axl potently inhibited proliferation of the resistant cells, and inhibitors to these kinases may provide additional options for the treatment of HER2-independent resistance in tumors.

引用

页码：11539 / 11552

页数：14

共 35 条

[1] Computing topological parameters of biological networks [J].

Assenov, Yassen ;

Ramirez, Fidel ;

Schelhorn, Sven-Eric ;

Lengauer, Thomas ;

Albrecht, Mario .

BIOINFORMATICS, 2008, 24 (02) :282-284

[2] Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [J].

Baselga, Jose ;

Bradbury, Ian ;

Eidtmann, Holger ;

Di Cosimo, Serena ;

de Azambuja, Evandro ;

Aura, Claudia ;

Gomez, Henry ;

Dinh, Phuong ;

Fauria, Karine ;

Van Dooren, Veerle ;

Aktan, Gursel ;

Goldhirsch, Aron ;

Chang, Tsai-Wang ;

Horvath, Zsolt ;

Coccia-Portugal, Maria ;

Domont, Julien ;

Tseng, Ling-Min ;

Kunz, Georg ;

Sohn, Joo Hyuk ;

Semiglazov, Vladimir ;

Lerzo, Guillermo ;

Palacova, Marketa ;

Probachai, Volodymyr ;

Pusztai, Lajos ;

Untch, Michael ;

Gelber, Richard D. ;

Piccart-Gebhart, Martine .

LANCET, 2012, 379 (9816) :633-640

[3] SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors [J].

Bertrand, Matthieu ;

Petit, Valerie ;

Jain, Ashish ;

Amsellem, Raymonde ;

Johansen, Terje ;

Larue, Lionel ;

Codogno, Patrice ;

Beau, Isabelle .

CELL CYCLE, 2015, 14 (03) :364-374

[4] Exploring mechanisms of acquired resistance to HER2 (human epidermal growth factor receptor 2)-targeted therapies in breast cancer [J].

Creedon, Helen ;

Byron, Adam ;

Main, Joanna ;

Hayward, Larry ;

Klinowska, Teresa ;

Brunton, Valerie G. .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2014, 42 :822-830

[5] Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data [J].

Dai, MH ;

Wang, PL ;

Boyd, AD ;

Kostov, G ;

Athey, B ;

Jones, EG ;

Bunney, WE ;

Myers, RM ;

Speed, TP ;

Akil, H ;

Watson, SJ ;

Meng, F .

NUCLEIC ACIDS RESEARCH, 2005, 33 (20) :e175.1-e175.9

[6] Open source clustering software [J].

de Hoon, MJL ;

Imoto, S ;

Nolan, J ;

Miyano, S .

BIOINFORMATICS, 2004, 20 (09) :1453-1454

[7] Subsets of epidermal growth factor receptors during activation and endocytosis [J].

Emlet, DR ;

Moscatello, DK ;

Ludlow, LB ;

Wong, AJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (07) :4079-4086

[8] An efficient procedure for protein extraction from formalin-fixed, paraffin-embedded tissues for reverse phase protein arrays [J].

Guo, Huifang ;

Liu, Wenbin ;

Ju, Zhenlin ;

Tamboli, Pheroze ;

Jonasch, Eric ;

Mills, Gordon B. ;

Lu, Yiling ;

Hennessy, Bryan T. ;

Tsavachidou, Dimitra .

PROTEOME SCIENCE, 2012, 10

[9] Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies [J].

Hanker, Ariella B. ;

Pfefferle, Adam D. ;

Balko, Justin M. ;

Kuba, Maria Gabriela ;

Young, Christian D. ;

Sanchez, Violeta ;

Sutton, Cammie R. ;

Cheng, Hailing ;

Perou, Charles M. ;

Zhao, Jean J. ;

Cook, Rebecca S. ;

Arteaga, Carlos L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (35) :14372-14377

[10] AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer [J].

Hickinson, D. Mark ;

Klinowska, Teresa ;

Speake, Georgina ;

Vincent, John ;

Trigwell, Cath ;

Anderton, Judith ;

Beck, Sarah ;

Marshall, Gayle ;

Davenport, Sara ;

Callis, Rowena ;

Mills, Elizabeth ;

Grosios, Konstantina ;

Smith, Paul ;

Barlaam, Bernard ;

Wilkinson, Robert W. ;

Ogilvie, Donald .

CLINICAL CANCER RESEARCH, 2010, 16 (04) :1159-1169

← 1 2 3 4 →