Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib

Abstract

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…86 Missense mutations represent the second-most common type of KIT exon 11 mutations in GISTs ( Table 2). These mutations cluster in 5= KIT exon 11 and almost exclusively involve KIT codons 557, 559, and 560 41,55,60,64,66,74,76,78,81,88,[90][91][92][93] ( Figure 7). The Val559Asp, Val560Asp, and Trp557Arg followed by Val559Ala, Val559Gly, and Leu576Pro are the most common missense mutations reported in KIT exon 11 ( Table 3).…”

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

“…Five potential resistance mechanisms are: functional resistance (exon 9 and WT KIT); genomic amplification and KIT overexpression (Bauer et al, 2005); acquisition of secondary mutations (e.g. V654A) (Chen et al, 2004); activation of alternate RTKs (Mahadevan et al, 2005a); and ATP-dependent IM efflux through ABCB1/ABCC1 transporters (Theou et al, 2005). Our strategy was to develop an IM-resistant GIST cell line and perform gene expression profiling (GEP) on GIST-S and GIST-R cells to identify marker(s) of IM resistance.…”

Improved Detection of KIT Exon 11 Duplications in Formalin-Fixed, Paraffin-Embedded Gastrointestinal Stromal Tumors

“…5,6,8,[12][13][14][15][16][17][18][19][20][21][22][23] All analyzed duplications, except two (2.1%), have been reported in the KIT region c.1729_1794 (g.75722_75787). Primers CK11.1F and CK11.3R closely flanking this region were used for PCR amplification of smaller products, yielding 129 bp in KIT-WT.…”