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 and Yoon-Koo Kang 2 1 Asan Institute for Life Science, Asan Medical Center, Seoul, Korea 2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 3 Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 4 Gachon Institute of Genome Medicine and Science, Gachon University Gil Hospital, Incheon, Korea * These authors contributed equally to this work Correspondence to: Yoon-Koo Kang, email: ykkang@amc.seoul.kr Keywords: gastrointestinal stromal tumor, patient-derived xenograft, KIT mutation, receptor tyrosine kinase inhibitors, resistance Received: April 07, 2017 Accepted: August 23, 2017 Published: September 11, 2017 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.