338 BM-1252 (APG-1252): a potent dual specific Bcl-2/Bcl-xL inhibitor that achieves complete tumor regression with minimal platelet toxicity

we investigated the in vitro cytotoxicity of inhibitors against different components of the PI3K/AKT/mTOR pathways in RICTOR-amplified lung cancer cells. Results: The majority of cells possess normal copy numbers of RICTOR but 3 out of 27 non-small cell lung cancer (NSCLC) cell lines, including H23 (adenocarcinoma) and H1703 (squamous), were found to have ratio of RICTOR/control around 2, suggesting RICTOR amplification in those cell lines. Genetic knockdown of RICTOR by using either siRNA or inducible shRNA was associated with growth inhibition of RICTOR-amplified lung cancer cell lines. The growth of xenograft lung tumor was also inhibited by inducible RICTOR knockdown. Among 6 different kinase inhibitors against the PI3K/AKT/mTOR pathways, agents blocking both mTOR1 and mTOR2 were the most active in RICTOR-amplified lung cancer cells. Conclusions: Targeted genetic blockade of RICTOR led to growth inhibition of RICTOR-amplified lung cancer cells, indicating that selective targeting of RICTOR may represent a novel therapeutic strategy for the treatment of this subgroupof lung cancer patients. Our study also provides the rationale for utilizing dual mTOR1/2 inhibitors as a potential therapy for lung cancer patients harboring RICTOR amplification.