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@article{Nunes:2016:10.18632/oncotarget.8504,
author = {Nunes, J and Zhang, H and Angelopoulos, N and Chhetri, J and Osipo, C and Grothey, A and Stebbing, J and Giamas, G},
doi = {10.18632/oncotarget.8504},
journal = {Oncotarget},
pages = {27599--27612},
title = {ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation},
url = {http://dx.doi.org/10.18632/oncotarget.8504},
volume = {7},
year = {2016}
}

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TY  - JOUR
AB  - 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.
AU  - Nunes,J
AU  - Zhang,H
AU  - Angelopoulos,N
AU  - Chhetri,J
AU  - Osipo,C
AU  - Grothey,A
AU  - Stebbing,J
AU  - Giamas,G
DO  - 10.18632/oncotarget.8504
EP  - 27612
PY  - 2016///
SN  - 1949-2553
SP  - 27599
TI  - ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation
T2  - Oncotarget
UR  - http://dx.doi.org/10.18632/oncotarget.8504
UR  - http://hdl.handle.net/10044/1/38498
VL  - 7
ER  -

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