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Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors 

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O R I G I N A L P A P E R

Molecular analysis of secondary kinase mutations

in imatinib-resistant gastrointestinal stromal tumors

Ken-Hong LimÆ Ming-Jer Huang Æ Li-Tzong Chen Æ

Tsang-En WangÆ Chien-Liang Liu Æ Cheng-Shyong Chang Æ Mei-Chin LiuÆ Reuy-Kuen Hsieh Æ Chin-Yuan Tzen

Received: 28 August 2007 / Accepted: 11 September 2007 / Published online: 6 October 2007  Humana Press Inc. 2007

Abstract Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study

the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12,

K.-H. Lim M.-J. Huang  R.-K. Hsieh

Division of Hematology and Oncology, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan

K.-H. Lim T.-E. Wang  C.-L. Liu  C.-Y. Tzen Mackay Medicine, Nursing and Management College, 92, Shengjing Road, Taipei 112, Taiwan

M.-J. Huang

School of Medicine, College of Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan L.-T. Chen

Department of Internal Medicine, Kaohsiung Medical University Hospital, 100, Tzyou 1st Road, Kaohsiung 807, Taiwan L.-T. Chen

Division of Cancer Research, National Health Research Institutes, Ward 191 Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan

T.-E. Wang

Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan

C.-L. Liu

Department of Surgery, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan

C.-S. Chang

Division of Hematology–Oncology, Department of Internal Medicine, Changhua Christian Hospital, 135, Nanhsiao Street, Changhua 500, Taiwan

C.-S. Chang

Department of Medical Education and Research, Changhua Christian Hospital, 135, Nanhsiao Street,

Changhua 500, Taiwan M.-C. Liu

Department of Medical Oncology, Koo Foundation Sun Yat-Sen Cancer Center, 125, Li-De Road, Taipei 112, Taiwan

C.-Y. Tzen (&)

Department of Pathology, Mackay Memorial Hospital, 45, Minsheng Road, Tamshui, Taipei 251, Taiwan

e-mail: jeffrey@ms2.mmh.org.tw C.-Y. Tzen

Department of Medical Research, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan C.-Y. Tzen

National Taipei College of Nursing, 365, Min-Te Road, Taipei 11257, Taiwan

C.-Y. Tzen

School of Medical Technology, Taipei Medical University, 250, Wu-Xin Street, Taipei 110, Taiwan

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14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The sec-ondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.

Keywords Gastrointestinal stromal tumors KIT  Platelet-derived growth factor receptor alpha Kinase mutation Imatinib  Secondary resistance

Introduction

Gastrointestinal stromal tumors (GISTs) are characterized by the expression of the KIT receptor. Activating KIT mutation or platelet-derived growth factor receptor alpha (PDGFRA) mutation has been found in the majority of GISTs, and has been linked to their molecular pathogenesis [1,2]. It is the most frequent mesenchymal gastrointestinal tumor with the annual incidence of approximately 10–20 cases per million population [3–5]. The annual incidence of GISTs in Taiwan is estimated to be 300 new cases [5]. Completed surgical resection remains the first line therapy for primary localized GIST. However, the median disease free survival following completed surgical resection for tumors larger than 5 cm in size is only 5 years [6].

Imatinib mesylate (Gleevec, Glivec; Novartis Pharma AG, Basel, Switzerland) is a rationally designed, orally available 2-phenylaminopyrimidine analogue. Imatinib blocks the activity of several tyrosine kinases including KIT and PDGFRA. Recurrent or metastatic GIST patients who are not responsive to conventional chemotherapy or radiotherapy show an excellent response to imatinib. Results from clinical trials have shown an overall response rate around 60% and progression arrest in 80–90% of patients [7]. However, most patients developed resistance to imatinib in a period of 2 years. Current evidences sug-gest that one of the mechanisms behind secondary imatinib resistance is related to additional mutations in the kinase domain of tumor genotype [8–18]. Therefore, we intend to identify the secondary kinase mutation in imatinib-resistant GISTs in a series of Taiwanese patients, and to study the relationship between secondary kinase mutations and the clinical response to imatinib.

Materials and methods Patients and specimens

From April 2001 to March 2006, 12 advanced GIST patients who have been treated with imatinib and have developed disease progression after initial response and emerged resistance to imatinib were included in this study. All patients received surgical excision of tumors after ini-tial diagnosis and received excision or biopsy of their progression lesions. Paraffin-embedded primary GIST tis-sues before imatinib therapy and progression lesions of the tumors after resistance to imatinib from all 12 patients were used in the genomic DNA analyses. The study was approved by the local institutional review board. All the tumor specimens were obtained with written informed consent.

DNA extraction

Briefly, representative paraffin blocks were cut in 8-lm slices using a clean disposable microtome blade for each block. To ensure representative sampling, excess tissue was trimmed before sectioning, and the first and the last sec-tions from each ribbon were examined by light microscope after routine hematoxylin and eosin staining. The paraffin sections were transferred directly to reaction tubes and incubated in 300 ll xylene at 25C for 5 min, pelleted at 12,000g for 5 min, resuspended in 300 ll of absolute alcohol at room temperature, spun down, and then lyoph-ilized. The pellets were then processed using a Puregene DNA isolation kit (Gentra, Minneapolis, MN, USA) according to the manufacturer’s instruction, which inclu-ded proteinase K (300 mg/ml) digestion overnight at 55C. The final extracts were dissolved in Tris Na2EDTA buffer and kept at 4C for later use.

Polymerase chain reaction (PCR) and DNA sequencing Four pairs of oligonucleotide primers were used to amplify exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. The primer pairs to amplify KIT were 9R (50-TGA CAT GGT CAA TGT TGG AA-30) and 9L (50-AGC CAG GGC TTT TGT TTT CT-30) for exon 9, 11R (50-TGG AAA GCC CCT GTT TCA TA-30) and 11L (50-CGT AAT CGT AGC TGG CAT GA-30) for exon 11, 13R (50-GCA AGA GAG AAC AAC AGT CTG G-30) and 13L (50-CAT GCG CTT GAC ATC AGT TT-30) for exon 13, and 17R (5’-TGA ACA TCA TTC AAG GGT ACT TTT G-30) and 17L (50-TTG AAA CTA AAA ATC CTT TGC AGG AC-30) for exon 17. The primer pairs to

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amplify PDGFRA were 10R (50-AGA TGG TTT GAG AGA TGG TAC TGC-30) and 10L (50-GGA CAC AGT AGA GTC CAA CAA CGT-30) for exon 10, 12F (50-TCC AGT CAC TGT CGCT GCT TC-30) and 12R (50-GCA AGG GAA AAG GGA GTC TT-30) for exon 12, 14R (50 -CTC ACT -CTC ATT CAA ACC TAT CAG C-30) and 14L (50-TC ATA CCC ATC TCC TAA CGG C-30) for exon 14, and 18F (50-ACC ATG GAT CAG CCA GTC TT-30) and 18R (50-TGA AGG AGG ATG AGC CTG ACC-30) for exon 18.

PCR was carried out according to previously described procedures [2, 19]. The PCR products were sequenced using the ABI PRISM BigDye terminator cycle sequencing ready reaction kit and ABI Prism 377 genetic analyzer (PE Applied Biosystems, Foster City, CA). All PCR products and independent duplicates were sequenced on both strands.

Statistical analysis

For statistical analysis, the v2test was conducted to analyze associations between kinase mutations and progression free survival (PFS). Statistical analysis was carried out using a commercially available computer program (SPSS; Chi-cago, IL). Significance was defined at P \ 0.05; all analyses were two sided.

Results Patients

The demographics of the 12 patients are summarized in Table1. There were eight male and four female patients, at an average age of 62 years (range, 48–88 years). The pri-mary tumor site was stomach in one patient, small intestine

in nine patients, and rectum in two patients. The dosage of imatinib ranged from 300 to 600 mg per day (case 5 took 300 mg due to grade IV eye lid edema, and cases 1, 6, 8, and 12 increased to 600 mg after disease progression). The overall average PFS after imatinib therapy is 17.5 months (range, 2–44 months). There are eight patients still alive with disease and four patients died of their diseases. Interestingly, although imatinib-resistant GIST tumors usually progressed after discontinuation of imatinib ther-apy, we have observed in case 3 that spontaneous partial regression of the metastatic hepatic tumor 9 weeks after the withdrawal of imatinib therapy (Fig.1).

Primary KIT mutations

Activating primary KIT mutations have been found in all but one of the primary tumors (Table2). Exon 11 muta-tions were found in eight cases (66.6%), including one missense mutation and eight deletions. Interestingly, one case harbored de novo double KIT exon 11 mutations including one missense mutation and one deletion (case 12). Exon 9 mutations were found in three cases (25%) and were all duplication of alanine-502 and tyrosine-503. One tumor was found to have wild-type sequences in all the exons examined (case 7). No primary mutation was found in exons 13 and 17 of KIT and in exons 10, 12, 14, and 18 of PDGFRA in this study.

Secondary KIT and PDGFRA mutations in imatinib-resistant GISTs

Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively (Table2). Five patients developed only one type of secondary KIT mutation in the first or second tyrosine kinase domain in 13

Table 1 Demographics of 12 patients with advanced GISTs

PFS, progression free survival; AWD, alive with disease; DOD, died of disease

No. Age/Sex Primary location Metastasis site PFS Outcome 1 56/M Duodenal Liver, Peritoneum 44 AWD 2 61/F Jejunum Liver, Peritoneum 16 DOD 3 56/F Small intestine Liver, Peritoneum 22 AWD

4 75/M Stomach Liver 24 DOD

5 59/M Rectum Liver, Peritoneum 18 AWD

6 51/F Rectum Liver, Lung 7 AWD

7 88/M Small intestine Liver 23 AWD 8 65/F Small intestine Liver, Peritoneum 25 AWD 9 48/M Small intestine Liver, Peritoneum 12 DOD 10 70/M Small intestine Liver, Peritoneum 2 DOD 11 65/M Small intestine Liver 8 AWD 12 51/M Small intestine Liver 36 AWD

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(n = 2) or 17 (n = 3), respectively. One patient (case 1) had two different secondary KIT missense mutations in exon 17 at the same codon, each from a different tumor sample (duodenum and liver). Another patient (case 8) had two different secondary KIT missense mutations in exons 13 and 17, each from a different tumor sample (jejunum and liver), and one wild-type tumor from the liver. Interest-ingly, one patients with primary KIT mutation developed secondary PDGFRA mutations in exons 14 (case 10). Notably, the secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before, either in untreated or imatinib-treated GIST, while the secondary PDGFRA exon 18 mutation V824V in case 11 represents a single nucleotide polymorphism. Wild-type KIT and PDGFRA sequences were found in two patients with primary KIT mutations in exons 9 (case 6) and 11 (case 9), respectively. In only one patient (case 7) with no detectable primary kinase mutation, a KIT missense mutation in exon 11 (V559A) was found. All the primary

mutation was always detectable along with the secondary mutation in each tumor. No more than two secondary mutations were found in the same tumor sample in this study. In summary, 8 (66.6%) of 12 patients with imatinib-resistant GISTs harbored one or more secondary kinase mutations in our series.

Correlation of KIT mutation and PFS

Although the mean PFS of GIST patients with primary KIT exon 11 mutation (23.63 months ± 11.86) was much longer than that of the patients with primary KIT exon 9 mutation (8.33 months), the PFS was not a significant difference between these two groups of patients in this study (P = 0.07, 95% confident interval –1.52, 32.1). Due to only one patient with wild-type KIT in our series, the difference of PFS between wild-type KIT and primary KIT exon 9 or exon 11 mutations could not be compared.

Discussion

In this study, acquired secondary mutations in KIT and PDGFRA in imatinib-resistant GISTs were found in 8 out of 12 patients (66.6%). Since KIT exon 11 V559A missense mutation should be sensitive to imatinib therapy, it should not be the secondary mutation responsible for imatinib resistance in case 7, and other mechanism of resistance should account for imatinib resistance in this case. It seems likely that this KIT exon 11 V559A mutation might have been missed in the primary tumor due to low-level muta-tions that were not detected by direct sequence analysis. Since mutational level that is less than 25% may not be detected by direct sequence analysis, the use of more sensitive techniques such as denaturing high performance liquid chromatography or cloning may improve the sensi-tivity of mutation detection in GISTs. All of our patients had initial response to imatinib therapy and received excision or biopsy of their progression lesions for study. The frequency of secondary kinase mutations after sec-ondary resistance to imatinib is high in our study, and is comparable to a recent study by Heinrich et al. [20]. Overall, the frequency of acquired secondary kinase mutations in GISTs with secondary resistance to imatinib ranges from 43.8% to 67% [11, 12, 17, 18]. However, GISTs with primary resistance to imatinib were found to have only 10% (1/10 patients) secondary kinase mutations [18]. This difference in frequency is significant, and may be due to the differences in the underlying biology of these two groups of GISTs.

Most acquired secondary KIT mutations are preferen-tially and nonrandomly located in the first or second

Fig. 1 Computed tomography of the abdomen of case 3. (a) Before discontinuation of imatinib showing a new hepatic metastatic tumor at the anterior aspect of hepatic dome (4.4· 3.1 cm). (b) 9 weeks after the withdrawal of imatinib showing spontaneous partial regression of the metastatic hepatic tumor (4.3· 1.8 cm)

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tyrosine kinase domains. Our results represent the first secondary kinase mutational report in GISTs from Asian and showed that the occurrence of secondary kinase mutations has no ethnical difference between Taiwanese and Caucasian populations. Additionally, there are no significant correlations between secondary mutation and primary mutation in GISTs. To date, all the reported acquired secondary KIT and PDGFRA mutations are single amino acid missense mutations. The substitution of single amino acid in mutated tyrosine kinase domain probably leads to a change in the three-dimensional receptor con-formation and modification of the ATP-binding pocket, therefore inhibits the binding of imatinib to the receptor [16]. Debiec-Rychter et al. [12] have demonstrated that most imatinib-resistant GISTs still have various levels of constitutive KIT autophosphorylation. In addition, Hein-rich et al. [18] have shown that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activa-tion of critical downstream signaling pathways. Hence, KIT-dependent resistant mechanism is the most important mechanism for imatinib resistance in GISTs. However, KIT-independent resistant mechanism is still noted in some GISTs [12], such as case 6 in this study, where total loss of KIT expression and wild-type KIT was found in the i-matinib-resistant tumor.

Recent studies of imatinib-resistant GISTs have dem-onstrated that clonal or polyclonal evolution has led to GISTs progression [17, 18]. In patients with GIST har-boring primary KIT kinase mutation, resistant subclones

containing an additional KIT or PDGFRA mutation emerge in the presence of imatinib. Interestingly, each tumor nodule under progression apparently developed an indi-vidual clonal evolution and most patients developed secondary mutation in only one kinase exon. However, Wardelmann et al. [17] reported that three patients devel-oped secondary mutations in two or three kinase exons in their cohort. The cases with more than one secondary KIT mutations had a comparable prognosis as those with only one or no secondary mutation. In our cohort, two patients harbored more than one secondary KIT mutations in dif-ferent progression sites. The correlation between occurrences of multiple KIT kinase mutations and primary KIT kinase mutation was unclear. In our series, there are four types of clonal or polyclonal evolution being observed. First, primary KIT mutation turns to secondary KIT mutation; second, primary KIT mutation turns to multiple KIT mutations; third, primary KIT mutation turns to wild type; and fourth, primary KIT mutation turns to secondary PDGFRA mutation. The underlying molecular mechanisms and the relationship of these clonal or poly-clonal evolutions between different kinase mutations may warrant further investigations.

The correlation of secondary KIT mutations with clinical behavior in imatinib-resistant GISTs is not very clear at present time. However, tumors with secondary KIT exon 13 V654A mutations were characterized by a more rapid progression phenotype. In case 3 of our series, tumor with secondary KIT exon 13 V654A mutation showed a more

Table 2 KITand PDGFRA sequences of pre-imatinib and imatinib-resistant GISTs No. Primary KIT

mutation site

Primary KIT mutation type Secondary mutation site

Secondary mutation type

Sample site

1 Exon 11 Del VQWKVVEEINGNNYVYIDPTQL 555–576V

KIT Exon 17 D820G Duodenum

D820Y Liver

2 Exon 9 Ins AY502–503 KIT Exon 17 N822K Liver 3 Exon 11 Del KVV558–560S KIT Exon 13 V654A Liver 4 Exon 11 Del WKVV557–560 KIT Exon 13 Insertion 643 nucleotide

A frameshift

Liver

5 Exon 11 Del WK557–558CE KIT Exon 17 N822K Liver 6 Exon 9 Ins AY502–503 Wild type None detected Liver 7 Wild type None detected KIT Exon 11 V559A Liver 8 Exon 11 Del VYIDPTQL569–576 Wild type None detected Liver

KIT Exon 13 V654A Jejunum KIT Exon 17 N822K Liver 9 Exon 11 Del MYE552–554K Wild type None detected Liver 10 Exon 9 Ins AY502–503 PDGFRA Exon 14 H687Y Pelvic 11 Exon 11 Del VEEINGNNYVYIDPTQL560–576 PDGFRA Exon 18 V824Va Jejunum 12 Exon 11 Del QWKVVEEINGNNYVYIDPT

556–574

KIT Exon 17 D820Y Liver

Exon 11 V553S

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rapid growth after escalated imatinib dose, and spontane-ous partial regression of the progression hepatic tumor after withdrawal of imatinib in this case is very impressive. We speculate that secondary KIT exon 13 mutations may have some advantage on preferential clonal proliferation under selection pressure of imatinib treatment. Further molecular studies are warranted to clarify the underlying mechanisms in this withdrawal phenomenon.

In contrast to secondary KIT kinase mutation, secondary PDGFRA kinase mutation is much less common in imati-nib-resistant GISTs. To our knowledge, only four cases have been reported including one case with PDGFRA exon 18 V824V single nucleotide polymorphism (case 11). It has been clearly shown that primary kinase mutations in KIT and PDGFRA are mutually exclusive in untreated GISTs [2, 21]. However, secondary PDGFRA exon 14 H687Y mutation was found in a GIST harboring a primary KIT exon 9 mutation in this study (case 10). This novel PDG-FRA exon 14 kinase mutation has never been reported and we did not detect this mutation in more than 200 GIST patients in our own series. We believe that this PDGFRA exon 14 H687Y mutation is not a polymorphism and is associated with secondary imatinib resistance. Another case of imatinib-resistant GIST with primary KIT exon 11 G565R mutation has also been found to have secondary PDGFRA exon 18 D842V mutation [12]. The PDGFRA exon 18 D842V mutation was also found to associate with secondary imatinib resistance in a GIST harboring a pri-mary PDGFRA exon 12 V561D mutation [18]. These cases demonstrated that secondary resistance to imatinib could occur through mutation of a different kinase. It is note-worthy that the activation of downstream signaling intermediates was similar in KIT-mutant and PDGFRA-mutant GISTs [2, 22]. This observation suggested that mutant PDGFRA provides oncogenic signals that parallel those of mutant KIT [21]. Hence, imatinib-resistant GISTs with primary KIT mutation and secondary PDGFRA mutation are still dependent on the KIT signaling pathway. In conclusion, our finding of an association between new emerged KIT and PDGFRA kinase mutations and disease progression is very impressive in Taiwanese patients. The occurrence of secondary kinase mutations in GISTs has ethnically no difference between Taiwanese and Caucasian populations. Our report on secondary kinase mutations in imatinib-resistant GIST patients indicated that acquisition of secondary kinase mutations might be the most important cause of developing late resistance to imatinib treatment. The identification of secondary kinase mutations in pro-gressive lesions under imatinib treatment can be used to demonstrate imatinib resistance and disease progression in GISTs. These secondary kinase mutations are particularly important in view of new therapeutic strategies including either surgical resection of individual progressive lesion,

treatment with other small molecules such as sunitinib malate (Sutent [previously known as SU11248], Pfizer, Inc., New York, New York) [23], or withdrawal of imatinib therapy. The full understanding of the molecular mecha-nism of oncogenesis and resistance in GISTs may also help gain new insight into and establish further comparable strategies in other cancer types.

Acknowledgment This study is supported in part by grant from Mackay Good Neighborhood Foundation.

References

1. Hirota S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–80. 2. Heinrich MC, et al. PDGFRA activating mutations in

gastroin-testinal stromal tumors. Science 2003;299:708–10.

3. Nilsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimati-nib mesylate era—a population-based study in western Sweden. Cancer 2005;103:821–9.

4. Tryggvason G, Gislason HG, Magnusson MK, Jonasson JG. Gastrointestinal stromal tumors in Iceland, 1990–2003: the ice-landic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer 2005;117:289–93. 5. Tzen CY, et al. Incidence of gastrointestinal stromal tumor: a

retrospective study based on immunohistochemical and muta-tional analyses. Dig Dis Sci 2007;52:792–7.

6. Lin SC, et al. Clinical manifestations and prognostic factors in patients with gastrointestinal stromal tumors. World J Gastroen-terol 2003;9:2809–12.

7. Demetri GD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80.

8. Chen LL, et al. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 2004;64:5913–9.

9. Tamborini E, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stro-mal tumor patient. Gastroenterology 2004;127:294–9.

10. Wakai T, et al. Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br J Cancer 2004;90:2059–61.

11. Antonescu CR, et al. Acquired resistance to imatinib in gastro-intestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182–90.

12. Debiec-Rychter M, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroen-terology 2005;128:270–9.

13. Tamborini E, et al. KIT/Val654 Ala receptor detected in one imatinib-resistant GIST patient. Cancer Res 2005;65:1115 (author reply 1115).

14. Wardelmann E, et al. Acquired resistance to imatinib in gastro-intestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol 2005;6:249–51.

15. Grimpen F, et al. Resistance to imatinib, low-grade FDG-avidity on PET, and acquired KIT exon 17 mutation in gastrointestinal stromal tumour. Lancet Oncol 2005;6:724–7.

16. McLean SR, et al. Imatinib binding and cKIT inhibition is abrogated by the cKIT kinase domain I missense mutation Val654Ala. Mol Cancer Ther 2005;4:2008–15.

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17. Wardelmann E, et al. Polyclonal evolution of multiple sec-ondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12: 1743–9.

18. Heinrich MC, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24: 4764–74.

19. Miettinen M, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinico-pathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 2003;27:625–41.

20. Heinrich MC, et al. Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status. J Clin Oncol 2006;24(Suppl 18):9502.

21. Corless CL, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23:5357–64.

22. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointes-tinal stromal tumors. J Clin Oncol 2004;22:3813–25.

23. Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–38.

數據

Table 1 Demographics of 12 patients with advanced GISTs
Fig. 1 Computed tomography of the abdomen of case 3. (a) Before discontinuation of imatinib showing a new hepatic metastatic tumor at the anterior aspect of hepatic dome (4.4 · 3.1 cm)
Table 2 KIT and PDGFRA sequences of pre-imatinib and imatinib-resistant GISTs No. Primary KIT

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