Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody, in a Panel of Gastrointestinal Stromal Tumor Xenograft Models

Abstract

We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST) xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived), treated for 3 weeks, and grouped as follows: control (untreated); CK6 (40 mg/kg, 3 × weekly); imatinib (50 mg/kg, twice daily); sunitinib (40 mg/kg, once daily); imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments). Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU) and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control), while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs) was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies.

Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations

“…Interestingly, in all xenografts tested, we observed a significant reduction in MVD in cabozantinib treated-tumors compared with the control and imatinib. Moreover, in previous studies published by our group, sunitinib, another multitarget TKI with anti-angiogenic properties, also resulted in a prominent increase in apoptotic activity in the UZLX-GIST4 model as compared with imatinib (27,28). In the UZLX-GIST2 and -GIST9 models, however, the antiangiogenic effect was not accompanied by a significant increase in apoptotic activity.…”

Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: analysis of clinicopathological characteristics related to engraftment success

“…UZLX-GIST9 harboring both primary and secondary mutations in KIT exons 11 and 17 was established from a metastatic lesion that showed clinical progression after treatment with imatinib, sunitinib, and regorafenib. GIST PDX models harboring primary mutation alone in either KIT exon 9 or exon 11 were also reported [12][13][14][15][16] . We have previously reported the establishment of 3 separate GIST PDX models -GIST-RX1 (mutations in KIT exons 11, 17, and PTEN from a patient with resistance to imatinib, sunitinib, and sorafenib), GIST-RX2 (mutations in KIT exons 11 and 14 from a patient with resistance to imatinib), and GIST-RX4 (mutations in KIT exons 9 and 17 from a patient with resistance to imatinib and sunitinib) 17 .…”

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

“…We established three GIST PDX models using tumor samples from patients who clinically progressed after treatment with current standard TKIs. In terms of mutation and drug resistance profiles, our PDX models are distinct from previously reported models [ 6 – 10 ]. Our GIST PDX models, GIST-RX1, GIST-RX2, and GIST-RX4, harbored secondary mutations in KIT exon 17 (p.D816E), exon 14 (p.T670I), and exon 17 (p.D820E), respectively, which have not been reported in prior studies.…”

“…To date, GIST PDX models have only been established in a few studies [ 6 – 11 ]. Among them, only two PDX models had both primary and secondary mutations in KIT exons 11 and 17 [ 6 – 10 ]. One model (UZLX-GIST9 with KIT p.P577del + W557LfsX5 + D820G mutation) was established from a metastatic lesion that showed clinical progression after imatinib, sunitinib, and regorafenib treatment and the other (PDX with p.Lys558_Glu562del and D816H mutation) was established from a metastatic lesion after the failure of imatinib.…”