Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA.
Cell Rep. 2024 Oct 22;43(10):114829. doi: 10.1016/j.celrep.2024.114829. Epub 2024 Oct 3.
Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.
小儿型高级别神经胶质瘤常携带涉及受体酪氨酸激酶基因的基因融合，包括神经营养型酪氨酸激酶受体（NTRK）融合。临床上，这些肿瘤对酪氨酸激酶抑制的初始反应率很高，但由于积累了额外的耐药性赋予突变，最终还是会复发。在这里，我们开发了一系列未经治疗和治疗过的 NTRK1/2/3 融合驱动的神经胶质瘤的基因工程小鼠模型。所有测试的 NTRK 融合在体内都是致癌的。NTRK 变体、N 端融合伙伴和耐药相关点突变都影响肿瘤组织学和侵袭性。额外的肿瘤抑制基因缺失大大增强了肿瘤的侵袭性。TRK 激酶抑制剂的治疗显著延长了 NTRK 融合驱动的神经胶质瘤小鼠的生存时间，但未能完全消除肿瘤，导致停药后复发。最后，我们表明 ERK 激活促进了对 TRK 激酶抑制的耐药性，并确定 MEK 抑制作为一种潜在的联合治疗方法。这些模型将是研究 NTRK 融合肿瘤治疗耐药性的宝贵工具。
