Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904, USA; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904, USA.
Cell Rep. 2020 Mar 10;30(10):3383-3396.e7. doi: 10.1016/j.celrep.2020.02.014.
SPRY2 is a purported tumor suppressor in certain cancers that promotes tumor growth and resistance to receptor tyrosine kinase inhibitors in glioblastoma. Here, we identify a SPRY2-dependent bypass signaling mechanism in glioblastoma that drives resistance to EGFR and MET inhibition. In glioblastoma cells treated with EGFR and MET inhibitors, SPRY2 expression is initially suppressed but eventually rebounds due to NF-κB pathway activation, resultant autocrine FGFR activation, and reactivation of ERK, which controls SPRY2 transcription. In cells where FGFR autocrine signaling does not occur and ERK does not reactivate, or in which ERK reactivates but SPRY2 cannot be expressed, EGFR and MET inhibitors are more effective at promoting death. The same mechanism also drives acquired resistance to EGFR and MET inhibition. Furthermore, tumor xenografts expressing an ERK-dependent bioluminescent reporter engineered for these studies reveal that this bypass resistance mechanism plays out in vivo but can be overcome through simultaneous FGFR inhibition.
SPRY2 是某些癌症中的假定肿瘤抑制因子，它促进神经胶质瘤中的肿瘤生长和对受体酪氨酸激酶抑制剂的耐药性。在这里，我们确定了神经胶质瘤中一种依赖 SPRY2 的旁路信号机制，该机制导致对 EGFR 和 MET 抑制的耐药性。在接受 EGFR 和 MET 抑制剂治疗的神经胶质瘤细胞中，SPRY2 的表达最初受到抑制，但由于 NF-κB 途径的激活、随后的 FGFR 自分泌激活以及 ERK 的重新激活，导致 SPRY2 转录的重新激活，SPRY2 的表达最终反弹。在 FGFR 自分泌信号不发生且 ERK 不会重新激活的细胞中，或者在 ERK 重新激活但 SPRY2 无法表达的细胞中，EGFR 和 MET 抑制剂更有效地促进细胞死亡。同样的机制也导致了对 EGFR 和 MET 抑制的获得性耐药性。此外，表达了为此项研究设计的依赖于 ERK 的生物发光报告基因的肿瘤异种移植物揭示了这种旁路耐药机制在体内发挥作用，但通过同时抑制 FGFR 可以克服这种耐药性。
