Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.

Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.

P1, N=20, Completed, Hangzhou Hanx Biopharmaceuticals, Ltd. | Active, not recruiting --> Completed

Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.

Our results showed that NUAK1 kinase controls mTOR subcellular localization and induces Akt phosphorylation, demonstrating that NUAK1 regulates the growth factor-dependent activation of Akt signaling. Therefore, targeting NUAK1, or co-targeting it with Akt or mTOR inhibitors, may be effective in cancers with hyperactivated Akt signaling.

P1, N=36, Recruiting, Onconova Therapeutics, Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

ARK5 and SIRT3 are overexpressed in RCC and associated with parameters of poor prognosis as well as short survival. Both seem to influence response to therapy in RCC. So, they could be new targets for therapy that may improve tumour response and patients' survival. There is a postulated relationship that needs more extensive investigation.

These results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.

We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy.

P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd. | Trial primary completion date: Apr 2023 --> Dec 2023

Moreover, it is demonstrated that HOTAIR crosstalk with miR-145-5p/NUAK1 during epigenetic regulation. Our findings indicate that HOTAIR/miR-145-5p/NUAK1 axis acts as an EMT regulator and may be candidate prognostic biomarker and targets for new therapies in liver cancer.

Previous studies have suggested that narazaciclib (ON123300), a second-generation, orally bioavailable and clinical-stage CDK4/6 inhibitor (CDKi), may trigger cell cycle arrest and significant tumor growth inhibition (TGI) in BTKi-resistant MCL models...When combined with ibrutinib, but not with the second generation therapeutic acalabrutinib, narazaciclib achieved significant synergistic antitumor activity in both BTK-sensitive and BTK-resistant cells... Narazaciclib, due to its completely distinct MoA from BTKi involving the direct modulation of the cell cycle, can achieve significant synergistic activity with ibrutinib in vitro and in vivo, especially in BTKi-resistant models of MCL. Ongoing phospho-proteomics and genetic edition assays will help deciphering the molecular bases of this unique drug cooperation at the cell cycle level. Encore Abstract - previously submitted to AACR 2023

P1/2, N=60, Recruiting, Onconova Therapeutics, Inc. | Not yet recruiting --> Recruiting

We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.

Docking data showed a higher affinity of narazaciclib with BUB1 compared to palbociclib and abemaciclib. Combination of narazaciclib with autophagy inhibitors sensitized several breast cancer cells to cell death. Narazaciclib treatment may promote antitumor immunity by influencing the expression of various immune modulators in the tumor cells which needs to be further validated in preclinical animal models; and ultimately in the clinic.

HX301 also suppressed AM7577 growth, likely due to the suppression of FLT3-ITD activity since we previously reported FLT3-ITD being the driver mutation in this model which responded to AC220, a FLT3 TKi...Further preclinical/translational studies are being conducted in order to reveal predictive biomarkers, in addition to FLT3 mutation and CSF1R expression/mutations. We believe that HX301 could be a potential candidate for treating subset of AML, warranting further clinical investigation.

Current drug treatments, including chemo-/target therapies (e.g., sorafenib), are usually ineffective among advanced HCC and with high toxicity...For example, doxorubicin, first-line chemotherapy for TACE, and transarterial chemoembolization for advanced HCC... Our preliminary results demonstrate that HX301 had strong antitumor activity in HCC PDX models expressing both ARK5 and c-Myc. HX301 has the potential to be a first-in-class ARK5i candidate for the treatment of advanced HCC with high expression of c-Myc, warranting further clinical investigation.

AMPK-like proteins are still undergoing further classification and may represent novel targets for targeted gynecologic cancer therapies. In this chapter, we describe the AMPK-like family of proteins and their roles in reproductive physiology and gynecologic cancers.

All data including HR and p values as well as the used cutoff values for all genes for both PFS and OS are provided to enable the ranking of future biomarker candidates across all genes. Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in serous ovarian cancer.

Kaplan-Meier survival analysis further confirmed that their expression influenced OS in GAD patients. Collectively, the 6 MRGs signature might be a reliable tool for assessing OS in GAD patients, with potential application value in clinical decision-making and individualized therapy.

P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd.

P1/2, N=60, Not yet recruiting, Onconova Therapeutics, Inc.

Furthermore, immunohistochemical analysis of 20 HCC clinical samples showed that the expression level of NUAK1 was positively correlated with DKK1 and p-Akt. Taken together, we provide the first evidence that DKK1 promotes NUAK1 transcriptional expression via the activation Akt in HCC.

Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes.

5-FU sensitivity was enhanced after circ_0003998 level reduction in vivo. These findings unraveled that circ_0003998 elevated 5-FU resistance in HCC by sponging miR-513a-5p to upregulate the level of ARK5, indicating that circ_0003998 might be used as a target to improve 5-FU therapy for HCC.

Knocking down NUAK1 decreased GC cell proliferation and migration but increased oxidative stress in vitro and inhibited the development of tumor in vivo, while miR-622 acted to suppress the action of NUAK1 through the miR-622/NUAK1/p-protein kinase B (Akt) axis, thereby inhibiting the occurrence of GC. miR-622 and NUAK1 demonstrated potential for being targets and biomarkers for GC treatment.

c-Maf has long been proposed as a promising therapeutic target of MM and a panel of small molecule compounds have been identified to downregulate c-Maf and display potent anti-myeloma activities. In the current article, we take a concise summary on the advances in c-Maf biology, pathophysiology, and targeted drug discovery in the potential treatment of MM.

Preliminary data show that the preclinical BALB/C mouse model of TNBC recapitulates the results obtained in vitro . Conclusion Our overall results highlighted the potential role of miR-622 as promising biomarker and as a therapeutic target for TNBC.

Furthermore, it significantly attenuated tumor growth in a mouse xenograft tumor model. Our results demonstrate that a novel NUAK1 inhibitor, KI-301670, exerts anti-tumor effects by directly suppressing cancer cell growth by affecting the PI3K/AKT pathway, suggesting that it could be a novel therapeutic candidate for pancreatic cancer treatment.

We hypothesize that the screens will identify components that enhance or attenuate the effect of NUAKs and will reveal any differential regulators and partners for NUAK1/2. Discovering novel cancer-relevant NUAK regulators will enhance our understanding of the tumor promoting roles of NUAKs and provide insights into how to target these kinases for better therapeutic outcomes.

Our results support the idea that NUAK1 and NF-κB signalling pathways together regulate ROS and inflammatory signalling, supporting cell survival during each step of HGSOC pathogenesis. We propose that their combined inhibition may be efficacious as a novel therapeutic strategy for advanced HGSOC.

We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.

However, these effects were partially neutralized by miR-424-5p inhibitors. LINC00922 increases the cell viability, migration, invasion and EMT process of HCC cells by regulating the miR-424-5p/ARK5 axis, and thus may serve as a potential target for targeted therapy.

On the other hand, hsa-miR-181b-5p was among the top upregulated miRNAs in response to TGFB1, which is also predicted to regulate CDKN1B, TNFRSF11B, SIM1, and ARSJ in the BT-549 model. Taken together, our data is the first to provide such in depth analysis of lncRNA and miRNA epigenetic changes in response to TGFβ signaling in TNBC.

No abstract available

In evaluating the association of LKB1-signaling pathway expression with relapse free survival of varying breast cancer tumors exposed to chemotherapy or treatment-naive tumors, our data provides baseline knowledge for understanding the pathway dynamics that affect survival and therefore are linked to pathology. This establishes a foundation for studying LKB1 targets with the goal of identifying druggable targets.