Phosphoinositide-dependent protein kinase 1 is a potential novel therapeutic target in mantle cell lymphoma

Maegawa, Saori; Chinen, Yoshiaki; Shimura, Yuji; Tanba, Kazuna; Takimoto, Tomoko; Mizuno, Yoshimi; Matsumura-Kimoto, Yayoi; Kuwahara-Ota, Saeko; Tsukamoto, Taku; Kobayashi, Tsutomu; Horiike, Shigeo; Kuroda, Junya

doi:10.1016/j.exphem.2017.12.006

Cited by 12 publications

(12 citation statements)

References 44 publications

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“…BX-912 is an inhibitor of 3-phosphoinositide-dependent protein kinase 1 PDK1/Akt signaling [ 37 ]. It is an experimental drug that has been studied for its potential therapeutic use in the treatment of breast, colon, and prostate cancers, as well as gliomas [ 38 ] and mantle cell lymphoma [ 39 ]. Daunorubicin, belonging to the anthracyclines class, is a chemotherapy drug for treating leukemias and Kaposi’s sarcoma [ 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

MicroRNA, mRNA, and Proteomics Biomarkers and Therapeutic Targets for Improving Lung Cancer Treatment Outcomes

Raese

Luo

et al. 2023

Cancers

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The majority of lung cancer patients are diagnosed with metastatic disease. This study identified a set of 73 microRNAs (miRNAs) that classified lung cancer tumors from normal lung tissues with an overall accuracy of 96.3% in the training patient cohort (n = 109) and 91.7% in unsupervised classification and 92.3% in supervised classification in the validation set (n = 375). Based on association with patient survival (n = 1016), 10 miRNAs were identified as potential tumor suppressors (hsa-miR-144, hsa-miR-195, hsa-miR-223, hsa-miR-30a, hsa-miR-30b, hsa-miR-30d, hsa-miR-335, hsa-miR-363, hsa-miR-451, and hsa-miR-99a), and 4 were identified as potential oncogenes (hsa-miR-21, hsa-miR-31, hsa-miR-411, and hsa-miR-494) in lung cancer. Experimentally confirmed target genes were identified for the 73 diagnostic miRNAs, from which proliferation genes were selected from CRISPR-Cas9/RNA interference (RNAi) screening assays. Pansensitive and panresistant genes to 21 NCCN-recommended drugs with concordant mRNA and protein expression were identified. DGKE and WDR47 were found with significant associations with responses to both systemic therapies and radiotherapy in lung cancer. Based on our identified miRNA-regulated molecular machinery, an inhibitor of PDK1/Akt BX-912, an anthracycline antibiotic daunorubicin, and a multi-targeted protein kinase inhibitor midostaurin were discovered as potential repositioning drugs for treating lung cancer. These findings have implications for improving lung cancer diagnosis, optimizing treatment selection, and discovering new drug options for better patient outcomes.

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Section: Resultsmentioning

confidence: 99%

MicroRNA, mRNA, and Proteomics Biomarkers and Therapeutic Targets for Improving Lung Cancer Treatment Outcomes

Raese

Luo

et al. 2023

Cancers

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“…High expression of KRAS was demonstrated to be resistant to docetaxel, a chemotherapeutic drug [ 49 ], RDEA119, and selumetinib which are all MAPK kinase (MEK) inhibitors [ 50 , 51 ] ( Figure 4 A). In addition, increased expression levels of MMP7 and CD44 were shown to be resistant to Bx-912, which is a phosphoinositide-dependent kinase 1 (PDK1) inhibitor [ 52 , 53 ], navitoclax (a Bcl-2 inhibitor) [ 54 , 55 ], and vorinostat (a histone deacetylase (HDAC) inhibitor) [ 56 , 57 ] ( Figure 4 B,C).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, increased expression levels of MMP7 and CD44 were shown to be related to resistance to Bx-912 (a PDK1 inhibitor) [ 52 , 53 ], navitoclax (a Bcl-2 inhibitor) [ 54 , 55 ], and vorinostat (an HDAC inhibitor) [ 56 , 57 ]. For further analysis, we determined the potential roles of the KRAS/MMP7/CD44 oncogenes as factors that influence high diagnostic efficacy in CRC patients; therefore, we explored a ROC analysis based on the TCGA database, on patients’ responses to chemotherapy treatment based on RECIST criteria, and results showed that patients with increased levels of these genes responded poorly to treatment ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Identification of Sulfasalazine’s Therapeutic Potential for Suppressing Colorectal Cancer Stemness and Metastasis through Targeting KRAS/MMP7/CD44 Signaling

et al. 2022

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Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene’s overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.

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“…This study is also the first to show the universal antitumor effect of the blockade of PDPK1 on BCLs, regardless of disease subtypes, in addition to MCL. 10 However, therapeutic targeting of PDPK1 may cause various unnecessary effects because PDPK1 regulates more than 20 downstream functional kinases associated with pleiotropic biological processes, such as immunity, bone formation, glucose metabolism, renal sodium transport, pH regulation, and mitochondrial activity. [25][26][27][28][29][30][31][32][33] The on-and/or off-target-related adverse events remain almost unavoidable in cancer treatment using the molecular-targeted kinase inhibitors [34][35][36] ; however, we attempted to select an effector molecule responsible for the oncogenic property of PDPK1 to preserve antilymphoma efficacy and to avoid unnecessary adverse events as much as possible.…”

Section: Discussionmentioning

confidence: 99%

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

Katsuragawa‐Taminishi,

Mizutani,

Kawaji‐Kanayama

et al. 2023

Cancer Science

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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.

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Phosphoinositide-dependent protein kinase 1 is a potential novel therapeutic target in mantle cell lymphoma

Cited by 12 publications

References 44 publications

MicroRNA, mRNA, and Proteomics Biomarkers and Therapeutic Targets for Improving Lung Cancer Treatment Outcomes

MicroRNA, mRNA, and Proteomics Biomarkers and Therapeutic Targets for Improving Lung Cancer Treatment Outcomes

Preclinical Identification of Sulfasalazine’s Therapeutic Potential for Suppressing Colorectal Cancer Stemness and Metastasis through Targeting KRAS/MMP7/CD44 Signaling

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

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