ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation.
Oncotarget
; 7(19): 27599-612, 2016 May 10.
Article
in En
| MEDLINE
| ID: mdl-27050377
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptor, ErbB-2
/
Vesicular Transport Proteins
/
Proto-Oncogene Proteins c-cbl
/
Trastuzumab
/
Autophagy-Related Proteins
/
Membrane Proteins
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Oncotarget
Year:
2016
Type:
Article
Affiliation country:
United kingdom