NESS - Novel KIT/CSF1R Inhibitor is Superior to Imantinib in a Spontaneous Mouse Model of Gastrointestinal Stromal Tumor (GIST)

Novel KIT/CSF1R Inhibitor is Superior to Imantinib in a Spontaneous Mouse Model of Gastrointestinal Stromal Tumor (GIST)
*Teresa S. Kim, MD, *Michael J. Cavnar, MD, *Eric C. Sorenson, MD, *Jonathan B. Greer, MD, *Noah A. Cohen, MD, *Adrian M. Seifert, MD, *Megan H. Crawley, BS, *Benjamin L. Green, BS, *Shan Zeng, MD, PhD, *Ronald P. DeMatteo, MD
Massachusetts General Hospital, Boston, MA

OBJECTIVE: GIST is the most common sarcoma and often harbors an activating KIT mutation. Imatinib mesylate is a tyrosine kinase inhibitor that targets KIT. It is effective against GIST, but rarely curative.

DESIGN: Randomized control study.

SETTING: Preclinical

PARTICIPANTS: 1) Transgenic mice that spontaneously develop GIST, 2) NOD-SCID-IL-2R?-null mice with subcutaneously implanted GIST-T1 xenografts.

INTERVENTIONS: Mice were randomized to receive control, imatinib, or PLX3397 for 1-4 weeks. Tumors were then weighed and analyzed by flow cytometry, western blot, and histology. GIST-T1 and HG129 GIST cell lines were treated with imatinib or PLX3397 in vitro and analyzed by colorimetric viability assay after 72 hours and western blot after 5 hours.

MAIN OUTCOME MEASURES: Tumor weight and histology.

RESULTS: In GIST mice treated for 4 weeks, imatinib decreased mean tumor weight by 74% of control (p<0.0001), while PLX3397 decreased mean tumor weight by 87% (p<0.0001 vs. control, p<0.05 vs. imatinib) (Fig. 1). By flow cytometry, PLX3397 decreased KIT+ tumor cells by 89% compared with imatinib (4.2x10^4 vs. 3.8x10^5 cells/tumor, p<0.05). H+E and Masson�s trichrome stain demonstrated hypocellularity and increased fibrosis in PLX3397- vs. imatinib-treated tumors (Fig. 2). Mechanistically, by immunoblot densitometry, PLX3397 decreased tumor phospho-KIT/KIT by 62% compared with control (p<0.05), while imatinib only decreased phospho-KIT/KIT by 39% (p<0.001). In vitro, PLX3397 more potently Novel Tyrosine Kinase Inhibitor PLX3397 is Superior to Imatinib in a Spontaneous Mouse Model of Gastrointestinal Stromal Tumor (GIST) reduced cell viability than imatinib, with 47% lower IC50 (24nM vs. 45nM, p<0.05), and similarly reduced phospho-KIT by western blot. Compared with imatinib, PLX3397 reduced tumor weight and KIT+ cells by 89% and 99.9% in GIST-T1 xenografts (p<0.01 and p<0.0001).

CONCLUSIONS: PLX3397 is more efficacious than imatinib in GIST and warrants testing in clinical trials.

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