Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 11;8(44):76712-76721.
doi: 10.18632/oncotarget.20816. eCollection 2017 Sep 29.

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

Young-Soon Na #  1 , Min-Hee Ryu #  2 , Changhoon Yoo  2 , Ju-Kyung Lee  1 , Jung Min Park  1 , Chae-Won Lee  1 , Sun Young Lee  1 , Young-Kyoung Shin  3 , Ja-Lok Ku  3 , Sung-Min Ahn  4 , Yoon-Koo Kang  2
Affiliations

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

Young-Soon Na et al. Oncotarget. .

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.

Keywords: KIT mutation; gastrointestinal stromal tumor; patient-derived xenograft; receptor tyrosine kinase inhibitors; resistance.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST None declared.

Figures

Figure 1
Figure 1. Immunohistochemical (IHC) analysis of original patient tumors and patient-derived xenograft (PDX) models
Hematoxylin and eosin (H&E) staining of patient tumor and PDX model samples and KIT immunostaining of tumors of PDX models. (A) GIST-RX1. (B) GIST-RX2. (C) GIST-RX4. 200× magnification.
Figure 2
Figure 2. Immunohistochemical (IHC) analysis of hematoxylin and eosin (H&E) staining and phosphatase and tensin homolog (PTEN) in original patient GIST-RX1 samples
(upper panel) Tumor obtained from pre-TKI. (lower panel) Tumor obtained from post-TKI which is TKI-resistant. Right bottom shows PTEN-positive endothelial cells of blood vessel and PTEN-negative tumor cells. 200× magnification.
Figure 3
Figure 3. Evaluation of response to receptor tyrosine kinase inhibitors (TKIs) in TKI-resistant gastrointestinal stromal tumor (GIST) patient-derived xenograft (PDX) models and imatinib-sensitive GIST-T1 xenograft models
Relative tumor growth was measured. (A) GIST-RX1, (B) GIST-RX2, (C) GIST-RX4, and (D) GIST-T1 xenografts. mpk, mg/kg.
Figure 4
Figure 4. Effects of imatinib, sunitinib, or regorafenib on the expression of KIT signaling-related proteins
(A) GIST-RX1, (B) GIST-RX2, (C) GIST-RX4, and (D) GIST-T1 xenografts. GIST, gastrointestinal stromal tumor; ERK, extracellular signal-regulated kinase; STAT, signal transducer and activator of transcription 3; mTOR, mechanistic target of rapamycin.
See this image and copyright information in PMC

References

    1. Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 2002;3:655–664. - PubMed
    1. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–580. - PubMed
    1. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–710. - PubMed
    1. Lim KH, Huang MJ, Chen LT, Wang TE, Liu CL, Chang CS, Liu MC, Hsieh RK, Tzen CY. Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors. Med Oncol. 2008;25:207–213. - PubMed
    1. Wang WL, Conley A, Reynoso D, Nolden L, Lazar AJ, George S, Trent JC. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor. Cancer Chemother Pharmacol. 2011;67:S15–24. - PubMed