RSK2 is a serine/threonine kinase downstream signaling mediator in the RAS/ERK signaling pathway and may be a therapeutic target in mantle cell lymphoma (MCL), an almost incurable disease subtype of non‐Hodgkin lymphoma. In this study, serine‐227 (RSK2 Ser227 ) in the N‐terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL‐derived cell lines and in tumor tissues derived from five MCL patients. BI‐D1870, an inhibitor specific to RSK2‐NTKD, caused RSK2 Ser227 dephosphorylation, and thereby, induced dose‐dependent growth inhibition via G 2 /M cell cycle blockade and apoptosis in four of the five cell lines, while one cell line showed only modest sensitivity. In addition, RSK2 gene knockdown caused growth inhibition in the four BI‐D1870‐sensitive cell lines. Comparative gene expression profiling of the MCL‐derived cell lines showed that inhibition of RSK2 Ser227 by BI‐D1870 caused downregulation of oncogenes, such as c‐MYC and MYB; anti‐apoptosis genes, such as BCL2 and BCL2L1; genes for B cell development, including IKZF1, IKZF3, and PAX5; and genes constituting the B cell receptor signaling pathway, such as CD19, CD79B, and BLNK. These findings show that targeting of RSK2 Ser227 enables concomitant blockade of pathways that are critically important in B cell tumorigenesis. In addition, we found favorable combinatory growth inhibitory effects of BI‐D1870 with inhibitors of BTK (ibrutinib), AKT (ipatasertib), and BCL2 (venetoclax) in cell characteristic‐dependent manners. These results provide a rationale for RSK2 Ser227 in the NTKD as a potential therapeutic target in MCL and for future development of a novel bioavailable RSK2 NTKD‐specific inhibitor.

Invasive fungal rhinosinusitis (FRS) is a rare but intractable infectious disease of the sinonasal region with destructive direct infiltration into surrounding tissues, such as the bone, orbit and brain, and potential dissemination to systemic organs. Symptomatic assessments and imaging are frequently not sufficiently diagnostic, and histopathological examination is essential for definite diagnosis of FRS. We herein report a case of chronic invasive FRS (CIFRS) in a 58-year-old Japanese male with end-stage diabetic nephropathy that required maintenance dialysis after graft rejection of living kidney transplantation. His initial main clinical presentation was sinus gangrene, which gradually progressed from the paranasal sinus to the nasal septum and oral palate, but not towards the intracranial or orbital region, for two months. The patient was first strongly suspected to have extranodal natural killer/T cell lymphoma (ENKTL), nasal type, a subtype of malignant lymphoma, based on the macroscopic appearance of the gangrene, expansion pattern and high serum soluble interleukin-2 level; however, repeated biopsies and eventual resection led to diagnosis of CIFRS due to Aspergillus niger and Mucor . The disease was improved by surgical resection in combination with antifungal pharmacologic treatment with liposomal amphotericin B and voriconazole. CIFRS typically occurs in immunocompetent patients and shows intracranial progression, but this case shows that atypical CIFRS with an uncommon expansion pattern can occur in an immunodeficient patient.

Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM.

Background: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting.Aims: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian

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