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

Changhoon Yoo,Yoon-Koo Kang,Jung Min Park,Ju-Kyung Lee,Chae-Won Lee,Min-Hee Ryu,Young-Soon Na,Young-Kyoung Shin,Sung-Min Ahn,Sun Young Lee,Ja-Lok Ku

doi:10.18632/oncotarget.20816

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 for studying TKI resistance mechanisms and evaluating novel targeted agents in GIST.

Highlights

The gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract
We demonstrated that the original patient and matched established tumors from the patient-derived xenograft (PDX) models exhibited the same histological features in the hematoxylin and eosin (H&E) staining and KIT IHC images (Figure 1)
We established three GIST PDX models using tumor samples from patients who clinically progressed after treatment with current standard tyrosine kinase inhibitors (TKIs)

Summary

Introduction

The gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST has activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRa) gene, which act as the main oncogenic drivers [1,2,3] and are harbored by 75–80% and approximately 10% of tumors, respectively. Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with advanced. Successful clinical trials have led to the approval of imatinib, sunitinib, and regorafenib for treating GISTs. most patients eventually develop disease progression with these drugs. Resistance to TKIs is linked to distinctive clinical and molecular features, and the development of secondary mutations in KIT or PDGFRa is the most common mechanism. Inter-/intra-tumoral genetic heterogeneity and clonal evolution with treatment in advanced disease www.impactjournals.com/oncotarget enable multiple secondary mutations to be detected in the same patient [5]. A better understanding of resistance of GISTs to TKIs is necessary to enhance the efficiency of drug development for TKI-refractory GISTs

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Results

Conclusion