ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2016-03-30
Date Acceptance
2016-03-18
Citation
Oncotarget, 2016, 7 (19), pp.27599-27612
ISSN
1949-2553
Publisher
Impact Journals
Start Page
27599
End Page
27612
Journal / Book Title
Oncotarget
Volume
7
Issue
19
Copyright Statement
This paper is available under a Creative Commons Attribution 3.0 License.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
breast cancer
trastuzumab
resistance
ATG9A
SILAC
BREAST-CANCER CELLS
MONOCLONAL-ANTIBODY
RECEPTOR
THERAPY
ERBB2
IDENTIFICATION
TRAFFICKING
SENSITIVITY
MECHANISMS
DISCOVERY
Publication Status
Published