Combined MEK and mTOR suppression is synergistic in human NSCLC and is mediated via inhibition of protein translation

Abstract

10615 Background: Lung cancer is a heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of RAS and AKT. These intersect at various points rendering the network highly redundant. Hence, dual suppression of both, using MEK and mTOR inhibitors may be a promising rational drug combination that can overcome the intrinsic plasticity of this signaling network. Methods: The concurrent combination of the MEK inhibitor CI-1040 and the mTOR inhibitor AP23573 was evaluated in non-small cell lung cancer (NSCLC) cell lines, using the combination index method of Chou and Talalay. The concurrent combination of Rapamycin and the MEK inhibitor PD0325901 was also evaluated in animal models of human lung cancer. Results: The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor rapamycin, or its analog AP23573, were synergistic in human lung cancer cell lines. Statistically significant enhancement of cell death by the combination of MEK and mTOR inhibitors was not observed. Rather, synergism was associated with suppression of proliferation and inhibition of protein translation. Concurrent suppression of both MEK and mTOR inhibited ribosomal biogenesis by forty percent after twenty-four hours and was associated with a block in the initiation phase of translation. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone, or PD0325901 at the maximum tolerated dose, in xenograft and human heterotransplanted lung tumor models grown in nude mice. Conclusions: These data support therapeutic strategies in lung cancer that simultaneously suppress RAS and mTOR signaling networks, and provide evidence that both pathways converge on factors that regulate protein translation initiation. No significant financial relationships to disclose.