Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

• Published in: Cancer science Vol. 114; no. 12; pp. 4691 - 4705
• Main Authors: Katsuragawa‐Taminishi, Yoko, Mizutani, Shinsuke, Kawaji‐Kanayama, Yuka, Onishi, Akio, Okamoto, Haruya, Isa, Reiko, Mizuhara, Kentaro, Muramatsu, Ayako, Fujino, Takahiro, Tsukamoto, Taku, Shimura, Yuji, Taniwaki, Masafumi, Miyagawa‐Hayashino, Aya, Konishi, Eiichi, Kuroda, Junya
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2023; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 4-Kinase - metabolism; 3-Phosphoinositide-Dependent Protein Kinases - metabolism; AKT; AKT protein; Apoptosis; B-cell lymphoma; Biotechnology industry; Burkitt's lymphoma; Carrier Proteins; Cell cycle; Cell Line; Cell Line, Tumor; Cell survival; Gene expression; Heat-Shock Proteins - metabolism; Humans; Kinases; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Malignancy; Medical prognosis; Myc protein; Original; Patients; Plasmids; Polo-like kinase 1; Protein kinase C; Protein Kinase Inhibitors - therapeutic use; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal protein S6 kinase; RSK2; S6K; Software; TAS0612; Therapeutic targets; TOR protein; Tumor suppressor genes; Tumor Suppressor Proteins - metabolism; S6K; AKT; TAS0612; RSK2; B-cell lymphoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15995

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. TAS0612 suppresses the growth of cell lines derived from various types of B‐cell lymphomas (BCLs). TAS0612 effectively induces the triple inhibition of RSK, AKT, and S6k and, thereby, leads to cell cycle arrest and apoptosis in cell lines derived from various types of BCLs.