Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the digestive tract and in some European regions the most frequently occurring mesenchymal malignancy, with an estimated incidence of 12–14.5 per million people[
1‐
3]. To date, surgery remains the cornerstone in the clinical management of primary resectable GISTs[
4]. However, surgery is not feasible in all patients because of tumour site, tumour size or due to metastatic spread[
5]. Among patients qualifying for primary surgery, 40-50% develops recurrence or metastases during follow-up. In the vast majority of GISTs, activating mutations in either the
KIT or the
PDGFRA (platelet derived growth factor receptor alpha) gene are the main oncogenic drivers[
6,
7]. These genes encode for receptor tyrosine kinases (RTKs), and activating mutations in the according genes can result in constitutive activation of intracellular signalling pathways leading to enhanced cell proliferation and -survival. The clinical significance of this observation is demonstrated by the exceptional anti-tumour activity of tyrosine kinase inhibitors (TKIs) in patients with advanced GISTs. Currently, imatinib is the standard first-line treatment for metastatic and unresectable GISTs and is very well tolerated in the vast majority of patients[
8]. Imatinib is a multi-targeted TKI inhibiting ABL, KIT and PDGFRA/B[
9]. Unfortunately, with time patients with imatinib-sensitive disease inevitably develop resistance to this agent. Sunitinib is the approved second-line therapy for patients intolerant or no longer responding to imatinib[
10]. Sunitinib is an oral multi-targeted TKI with activity against RTKs like KIT, VEGFR1/2/3 (vascular endothelial growth factor receptor) and PDGFRA/B, and was shown to increase progression-free survival as compared to placebo in imatinib-refractory patients in a clinical phase 3 trial[
11‐
13]. Nevertheless, with time the majority of patients will also develop progressive disease under treatment with sunitinib[
14]. Recently, regorafenib has been approved by the United States Food and Drug Administration (FDA) as third-line treatment for patients with advanced GIST after failure of both described TKIs. Regorafenib is an orally bioavailable multi-targeted TKI with known activity against KIT, RET (rearranged during transfection), VEGFR1/2/3, PDGFRβ, FGFR (fibroblast growth factor receptor)[
15]. In a very recent randomized phase 3 clinical trial regorafenib yielded a significantly better median progression-free survival than placebo (4.8
versus 0.9 months), in this setting[
16]. When analysing the available phase 3 evidence for all three established agents, it is obvious that the time to progression decreases progressively with every line of TKI treatment. It seems unlikely that the development of further KIT- or PDGFRA-targeted TKIs will circumvent the occurrence of heterogeneous TKI resistance in GISTs[
17]. In the majority of resistant GISTs, TKI resistance is mediated by the occurrence of secondary mutations in
KIT or
PDGFRA[
17]. Some additional resistance mechanisms have been described, like genomic amplification of
KIT or
PDGFRA genes or a switch of KIT dependency to other RTKs (e.g., AXL)[
18]. Hence, the development of novel GIST research models characterized by different sensitivity to standard treatments is very important for the testing of novel treatment approaches. At present, there are no GIST xenograft models described in the literature that have shown resistance to multiple TKIs. For this reason we are trying to develop novel GIST xenograft models reflecting the resistance pattern observed in the clinic. Our new model UZLX-GIST9 is derived from a patient clinically and radiologically progressing after treatment with imatinib, sunitinib, and regorafenib. In the current study, we have characterized this model and tested its sensitivity
in vivo to standard treatments.