Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors

Oncotarget
Young-Soon NaYoon-Koo Kang

Abstract

Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models for effective drug development. These were PDX models harboring primary and secondary KIT and additional mutations; KIT exon 11 (p.Y570_L576del), KIT exon 17 (p.D816E), and PTEN (p.T321fs) mutations in GIST-RX1 from a patient who was unresponsive to imatinib, sunitinib, and sorafenib, and KIT exon 11 (p.K550_splice) and KIT exon 14 (p.T670I) mutations in GIST-RX2 and KIT exon 9 (p.502_503insYA) and KIT exon 17 (p.D820E) mutations in GIST-RX4 from patients with imatinib and imatinib/sunitinib resistance, respectively. The histological features and mutation statuses of GIST PDXs were consistent with those of the original patient tumors, and the models showed TKI sensitivity comparable to clinical responses. Imatinib inhibited the KIT pathway in imatinib-sensitive GIST-T1 but not GIST-RX1, RX2, and RX4. These GIST PDX models will be useful f...Continue Reading

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Citations

Sep 14, 2019·Cancer Cell International·Alec R AndrewsChristene A Huang

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Methods Mentioned

BETA
xenografts
xenograft
exome sequencing
biopsy
surgical
PCR
electrophoresis
genotyping

Software Mentioned

Oncotator
Burrows Alignment ( BWA )
Mutect
OncoMap
Genome Analysis Toolkit ( GATK )

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