Cas-L was over-expressed in imatinib-resistant gastrointestinal stromal tumor cells

Abstract

2

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in

the gastrointestinal tract.  Most GISTs patients respond to imatinib, yet will eventually

exhibit resistance, and the mechanisms of imatinib resistance have not yet been fully

elucidated.  

To clarify the mechanisms of secondary imatinib-resistant gastrointestinal stromal

tumors, we generated resistant cells from the imatinib-sensitive GIST-T1 cells by

exposing them to increasing concentrations of imatinib for 6 months.  GIST-T1 IR

(imatinib-resistant) cells showing an IC50 of imatinib 5-7 µM were generated.  In GIST-

T1 IR cells, KIT and its downstream signaling molecules remained phosphorylated with

the presence of 1 µM imatinib, and no new mutations were found in KIT, PDGFRA,

PKCθ and JAK2.   DNA micro-array analysis showed the over-expression of Cas-L in

the resistant cells with 513 fold higher than that in the parental cells.  Cas-L over-

expression and SRC hyper-activation were also observed in the resistant cells at protein

level and they were markedly decreased in KIT siRNA transfected GIST-T1 IR cells. 

Interestingly, GIST-T1 IR cells transfected with Cas-L siRNA turned out to become

again sensitive to imatinib.  Imatinib or PP1, a SRC inhibitor, alone was not enough to

suppress the activation of KIT and its downstream signaling molecules, but the

combination of them showed strong inhibitory effects on those in the resistant cells.  

We report for the first time that the mechanism of imatinib-resistant GISTs, at least in

one cell line, involves KIT/Cas-L/SRC signaling.  Cas-L depletion sensitized the

resistant GIST-T1 IR cells to imatinib.