The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma

Abstract

Background Glioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood–brain barrier penetration and has potential for the treatment of brain tumors. Methods In this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model. Results AZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells. Conclusion AZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models . AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291. Electronic supplementary material The online version of this article (10.1186/s13046-019-1235-7) contains supplementary material, which is available to authorized users.

Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits EGFR/ERK/NF‐κB‐mediated anti‐apoptotic potential in glioblastoma

“…ERK activation was expressed and associated with aberrant EGFR expression in glioblastoma 37 . AZD9291, the third‐generation EGFR inhibitor, reversed primary resistance via alleviating EGFR/ERK signaling in glioblastoma in vitro and in vivo 38 . In our data, we shown both hyperforin and EGFR inhibitor (erlotinib) significantly reduced protein levels of p‐EGFR and p‐ERK in U87 and GBM‐8401 cells (Figure 2G‐K).…”

Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches

“…This drug has better activity and selectivity than the previous inhibitors. The drug has a better capacity to inhibit proliferation and prolongs the survival of GB cells [40]. Since 2018, the drug is being tested in a phase I/phase II clinical trial [41].…”

Mechanisms of EGFR Resistance in Glioblastoma

“…Its clinical tolerability and superior efficacy against T790M over second generation inhibitors such as afatinib is a direct consequence of this design. Despite this, preclinical studies report possible efficacy in glioblastoma [ 85 , 86 ].…”