Imatinib resistance in gastrointestinal stromal tumors

Chen, Lei L.; Sabripour, Mahyar; Andtbacka, Robert H.I.; Patel, Shreyaskumar; Feig, Barry W.; Macapinlac, Homer A.; Choi, Haesun; Wu, Elsie F.; Frazier, Marsha L.; Benjamin, Robert S.

doi:10.1007/s11912-005-0053-6

Cited by 38 publications

(9 citation statements)

References 30 publications

(22 reference statements)

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“…Overexpression of BAMBI inhibits the response of tumor cells to TGF-b and suggests that bcatenin interferes with TGF-b-mediated growth arrest by inducing the expression of BAMBI (Sekiya et al, 2004) that may contribute to an invasive GIST phenotype. Acquired mutations leading to IM resistance involve mis-sense mutations in the kinase domain of c-Kit, including Thr670Ile, Tyr823Asp and Val654Ala (Chen et al, 2005;McLean et al, 2005) that are sensitive to PKC412, a novel tyrosine kinase inhibitor (DebiecRychter et al, 2005). A study of 31 GIST patients were treated with IM and then underwent surgery: 13 were sensitive to IM, three had primary resistance and 15 had acquired resistance after initial benefit.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…66,142 Initial studies showed that secondary KIT mutations occur in the allele that harbors primary gain-offunction KIT mutation and in a great majority of cases represents missense point mutation affecting the first or second tyrosine kinase domain ( Figure 9). 66,89,[143][144][145] Subsequently, polyclonal evolution of multiple secondary KIT mutations has also been reported.…”

Section: Secondary Kit and Pdgfra Mutations Acquired During Imanitib-mentioning

confidence: 99%

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

Lasota

Miettinen

2006

Seminars in Diagnostic Pathology

276

258

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“…10,11 Resistance to imatinib has emerged, most commonly because of a new second (or acquired) mutation in the kinase domain. [12][13][14][15][16] GISTs show a predilection for liver metastasis and peritoneal implants-in vivo clones, and therefore provide an excellent model for studying the tumor biology. The histologic types of GISTs vary from very low grade to highly aggressive, and mitotic count vary more than 20-fold, To understand tumor progression, longitudinal follow-up of clonal evolution and comparison of primary tumor and subsequent recurrences within the same patient is probably the best means of circumventing both the interpatient variations and the complex events associated with late-stage advanced tumor progression.…”

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Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

et al. 2008

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Activating mutation in KIT or platelet-derived growth factor-a can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6-13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S-and G 2 phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination. Keywords: homozygous KIT mutation; GIST; SNP Gastrointestinal stromal tumors (GISTs) originate from the interstitial cells of Cajal and are driven by a proliferative signal resulting from dominant activating mutations of KIT or platelet-derived growth factor receptor-a (PDGFRA).

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Imatinib resistance in gastrointestinal stromal tumors

Cited by 38 publications

References 30 publications

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

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

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

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