Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Clin Cancer Res. 2017 Sep 15;23(18):5527-5536. doi: 10.1158/1078-0432.CCR-17-0478. Epub 2017 Jun 19.
The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat -amplified SQLC. However, only about 11% of such -amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells. To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors. The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified amplification and deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal amplifications in 3 of 20 (15%) primary human -amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors. We provide evidence for the existence of diverse mechanisms of primary drug resistance in -amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. .
8p12-p11 基因座在鳞状细胞肺癌 (SQLC) 中经常扩增；受体酪氨酸激酶成纤维细胞生长因子受体 1 (FGFR1) 是该扩增的最主要靶标之一。因此，已采用抑制 FGFR 的小分子来治疗扩增的 SQLC。然而，只有约 11%的此类扩增肿瘤对单一 FGFR 抑制有反应，并且一些肿瘤表现出肿瘤缩小不足，这与存在耐药肿瘤细胞相符。为了研究对 FGFR 抑制的耐药可能机制，我们研究了肺癌细胞系 DMS114 和 H1581。这两个细胞系对三种不同的 FGFR 抑制剂均高度敏感，但在治疗下仍保持持续的残留细胞活力，表明存在耐药细胞亚群。我们通过用恒定高剂量的 FGFR 抑制剂处理细胞来分离这些亚群。FGFR 抑制剂耐药细胞呈交叉耐药性，并表现出持续的 MAPK 通路激活。在耐药性 H1581 细胞中，我们发现扩增和缺失，导致 MAPK 通路重新激活。此外，我们在 20 个（15%）原发性人 -扩增 SQLC 标本中的 3 个中检测到亚克隆扩增。相比之下，耐药性 DMS114 细胞表现出 MAPK 通路重新激活的转录上调。因此，我们证明合理的联合治疗可使耐药细胞重新对 FGFR 抑制剂治疗敏感。我们为 -扩增肺癌中存在多种原发性耐药机制提供了证据，并提供了通过联合治疗改善 FGFR 抑制剂治疗的合理策略。
