Takako T Sano, Shinji S Takeuchi, Takayuki T Nakagawa, Daisuke D Ishikawa, Shigeki S Nanjo, Tadaaki T Yamada, Takahiro T Nakamura, Kunio K Matsumoto, Seiji S Yano


Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR-TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC-9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC-9 and HCC827 cells in vitro, irrespective of the presence or the absence of HGF. Using a xenograft model of severe combined immunodeficient mice with HGF-gene-transfected PC-9 cells (PC-9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor-cell proliferation and angiogenesis of PC-9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.