A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation.
A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation.
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一种新型的SND1-BRAF融合通过[校正] MAPK激活在GTL16细胞中对C-MET抑制剂PF-04217903的抗性。
DOI：
10.1371/journal.pone.0039653
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ching KA
中科院分区：
文献类型：
--
作者：
Lee NV;Lira ME;Pavlicek A;Ye J;Buckman D;Bagrodia S;Srinivasa SP;Zhao Y;Aparicio S;Rejto PA;Christensen JG;Ching KA
基于非临床和新出现的临床发现，靶向具有扩增或异常激活的c-Met（肝细胞生长因子受体）的癌症可能具有治疗益处。然而，耐药肿瘤的最终出现激发了对临床耐药的潜在机制的先发制人的鉴定。我们使MET扩增的胃癌细胞系GTL 16对c-Met抑制剂PF-04217903（METi）的长期暴露具有耐药性。对存活细胞的表征发现了7 q32和7 q34之间放大的染色体重排，该重排过表达组成型活性SND 1-BRAF融合蛋白。在抗性克隆中，通过SND 1-BRAF的下游MAPK通路的超活化赋予对c-Met受体酪氨酸激酶抑制的抗性。METi和RAF抑制剂PF-04880594（RAFi）联合治疗可抑制ERK活化，并避免对任一单一药物的耐药性。或者，用MEK抑制剂PD-0325901（MEKi）单独处理有效地阻断ERK磷酸化并抑制细胞生长。我们的研究结果表明，c-Met酪氨酸激酶抑制剂与BRAF或MEK抑制剂的组合可能有效治疗使用活化BRAF逃避c-Met信号转导抑制的耐药肿瘤。
Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a MEK inhibitor, PD-0325901 (MEKi) alone effectively blocked ERK phosphorylation and inhibited cell growth. Our results suggest that combination of a c-Met tyrosine kinase inhibitor with a BRAF or a MEK inhibitor may be effective in treating resistant tumors that use activated BRAF to escape suppression of c-Met signaling.
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影响因子：
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通讯作者：
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