Bay846, a new irreversible small molecule inhibitor of EGFR and Her2, is highly effective against malignant brain tumor models
The epidermal growth factor receptor (EGFR) pathway is aberrantly activated in tumors and plays a key role in promoting tumor growth. Small molecule inhibitors which bind reversibly to EGFR have demonstrated limited clinical activity. Thus, there is a continued need to develop novel EGFR inhibitors with improved anti-tumor activity. Bay846 is a newly developed small molecule inhibitor that binds irreversibly to the tyrosine kinase domains of EGFR and Her2. The in vitro and in vivo efficacy of Bay846 was tested using a panel of nine human malignant brain tumor (glioma) models. Lapatinib, a reversible inhibitor of EGFR and Her2, was included for comparison. Six glioma cell lines were sensitive to Bay846 treatment. Bay846 strongly suppressed tumor cell growth in vitro by inducing cell lysis/death rather than cell cycle arrest. Consistent with this, Bay846 had potent anti-tumor activity which led to regressions in tumor size. The active, phosphorylated form of EGFR was reduced by Bay846 treatment in vitro and in tumors. Importantly, the efficacy of Bay846 was significantly greater than lapatinib in all assays. Bay846-sensitivity was associated with expression of a wild-type PTEN in conjunction with high levels of an oncogenic EGFR variant (A289V or EGFRvIII). These studies demonstrate that targeting the EGFR pathway with the irreversible inhibitor Bay846 has great potential to increase the efficacy of this cancer therapy.
KeywordsEGFR Her2 Inhibitor Glioma Lapatinib
Financial support was provided by Bayer Healthcare (DEP and GWC), an American Cancer Society Institutional Research grant from the Upstate Cancer Institute at SUNY Upstate Medical University (DEP), and the Dept. of Neurosurgery at SUNY Upstate Medical University. We thank Bayer Healthcare for providing Bay846, Rebecca Sager for assistance with the LDH studies, and Ed Shillitoe for critical reading of the manuscript.
Bayer Healthcare (DEP and GWC), an American Cancer Society Institutional Research grant from the Upstate Cancer Institute at SUNY Upstate Medical University (DEP), and Dept. of Neurosurgery, SUNY Upstate Medical University.
Conflict of Interest
The authors declare that financial support and the Bay846 compound was provided by Bayer Healthcare. KP, HS, and OP are employees of Bayer Healthcare. The commercial funder had no role in the analysis or interpretation of data.
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