Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancer Discov. 2012 Oct;2(10):934-47. doi: 10.1158/2159-8290.CD-12-0103. Epub 2012 Sep 7.
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP-ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non-small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.
表皮生长因子受体 (EGFR) 激酶抑制剂的临床疗效受到耐药性发展的限制。不可逆的 EGFR 激酶抑制剂 WZ4002 对由 EGFR T790M 突变介导的最常见耐药机制有效。在这里，我们在多个互补模型中表明，对 WZ4002 的耐药性是通过细胞外信号调节激酶 (ERK) 信号的异常激活而发展的，这种异常激活是由丝裂原激活的蛋白激酶 1 (MAPK1) 的扩增或 ERK 信号的负调节剂的下调引起的。抑制 MAP-ERK 激酶 (MEK) 或 ERK 可恢复对 WZ4002 的敏感性并防止耐药性的出现。我们进一步在一名厄洛替尼耐药的 EGFR 突变型非小细胞肺癌患者中鉴定出 MAPK1 扩增。此外，WZ4002 耐药的 MAPK1 扩增细胞还表现出 EGFR 内化增加和对细胞毒性化疗药物敏感性降低。我们的研究结果提供了对 EGFR 激酶抑制剂耐药机制的深入了解，并强调了应在临床试验中评估的合理联合治疗方法。
