Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer

被引：46

作者：

Adam-Artigues, Anna ^{[1
]}

Arenas, Enrique J. ^{[2
,3
]}

Martinez-Sabadell, Alex ^{[2
]}

Braso-Maristany, Fara ^{[4
,5
]}

Cervera, Raimundo ^{[1
]}

Tormo, Eduardo ^{[1
,3
]}

Hernando, Cristina ^{[1
,6
]}

Teresa Martinez, Maria ^{[1
,6
]}

Carbonell-Asins, Juan ^{[1
]}

Simon, Soraya ^{[6
]}

Poveda, Jesus ^{[6
]}

Moragon, Santiago ^{[6
]}

Zazo, Sandra ^{[7
]}

Martinez, Debora ^{[4
,5
]}

Rovira, Ana ^{[3
,8
,9
]}

Burgues, Octavio ^{[1
,3
,10
]}

Rojo, Federico ^{[3
,7
]}

Albanell, Joan ^{[3
,8
,9
,11
]}

Bermejo, Begona ^{[1
,3
,6
]}

Lluch, Ana ^{[1
,3
,6
,12
]}

Prat, Aleix ^{[4
,5
,13
]}

Arribas, Joaquin ^{[2
,3
,9
,14
,15
]}

Eroles, Pilar ^{[1
,3
,16
]}

Miguel Cejalvo, Juan ^{[1
,3
,6
]}

机构：

[1] INCLIVA Biomed Res Inst, Valencia 46010, Spain

[2] Vall dHebron Inst Oncol VHIO, Preclin Res Program, Barcelona 08035, Spain

[3] Ctr Biomed Network Res Canc CIBERONC, Madrid 28019, Spain

[4] August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain

[5] Hosp Clin Barcelona, Dept Med Oncol, Barcelona 08036, Spain

[6] Hosp Clin Univ Valencia, Dept Med Oncol, Valencia 46010, Spain

[7] IIS Fdn Jimenez Diaz, Dept Pathol, Madrid 28040, Spain

[8] Hosp del Mar, Dept Med Oncol, Barcelona 08003, Spain

[9] IMIM Hosp del Mar Med Res Inst, Canc Res Program, Barcelona 08003, Spain

[10] Hosp Clin Univ Valencia, Dept Pathol, Valencia 46010, Spain

[11] Pompeu Fabra Univ UPF, Barcelona 08002, Spain

[12] Univ Valencia, Dept Med, Valencia 46010, Spain

[13] SOLTI Breast Canc Res Grp, Barcelona 08008, Spain

[14] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, Barcelona 08193, Spain

[15] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona 08010, Spain

[16] Univ Valencia, Dept Physiol, Valencia 46010, Spain

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 20期

关键词：

RECEPTOR TYROSINE KINASES; TO-MESENCHYMAL TRANSITION; AXL; ACTIVATION; CELLS; TRASTUZUMAB; INHIBITION; MECHANISM; EGFR; CHEMOTHERAPY;

D O I：

10.1126/sciadv.abk2746

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.

引用

页数：18

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