Oncotarget

Research Papers:

ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation

Joao Nunes, Hua Zhang, Nicos Angelopoulos, Jyoti Chhetri, Clodia Osipo, Arnhild Grothey, Justin Stebbing and Georgios Giamas _

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Oncotarget. 2016; 7:27599-27612. https://doi.org/10.18632/oncotarget.8504

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Abstract

Joao Nunes1,*, Hua Zhang1,*, Nicos Angelopoulos1, Jyoti Chhetri1, Clodia Osipo2, Arnhild Grothey3, Justin Stebbing1, Georgios Giamas1,3

1Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK

2Department of Microbiology and Immunology, Cardinal Bernardin Cancer Center of Loyola University Chicago, Health Sciences Division, Maywood, Illinois, USA

3School of Life Sciences, University of Sussex, Brighton, UK

*These authors have contributed equally to this work

Correspondence to:

Georgios Giamas, e-mail: [email protected]

Keywords: breast cancer, trastuzumab, resistance, ATG9A, SILAC

Received: January 04, 2016     Accepted: March 18, 2016     Published: March 30, 2016

ABSTRACT

Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474). This was accompanied by a reduction of Her2 protein levels and AKT phosphorylation (S473), as well as a decrease in Her2 stability, which was also observed in JIMT1 and MDA-453, naturally trastuzumab-resistant cells. In addition, ATG9A indirectly promoted c-Cbl recruitment to Her2 on T1112, a known c-Cbl docking site, leading to increased K63 Her2 polyubiquitination. Whereas silencing c-Cbl abrogated ATG9A repressive effects on Her2 and downstream PI3K/AKT signaling, its depletion restored BT474-TR proliferative rate. Taken together, our findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. This study identifies ATG9A as a potentially druggable target to overcome resistance to anti-Her2 blockade.


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