TAS-0612

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.

B‐cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide‐dependent kinase‐1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL‐derived cell lines examined, including those from activated B‐cell‐like diffuse large B‐cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient‐derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.