Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells.

BACKGROUND: 5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy. METHODS: Here, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour. RESULTS: Quantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures. CONCLUSIONS: AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.

Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226.

The heterogeneous transition state of resistance to RET kinase inhibitors converges on ERK1/2-driven Aurora A/B kinases.

AIM: While most patients with RET-altered cancer responded to the RET protein tyrosine kinase inhibitors (TKIs) pralsetinib (BLU667) and selpercatinib (LOXO292), few achieved a complete response. Heterogeneity in residual tumors makes it difficult to target their diverse genetic alterations individually. The aim of this study is to characterize the cancer cells that persist under continuous RET TKI treatment and identify the shared vulnerability of these cells. METHODS: We analyzed residual RET-altered cancer cells under prolonged RET TKI treatment by whole exome sequencing (WES), RNA-seq analysis, and drug-sensitivity screening. These were followed by tumor xenograft experiments of mono- and combinational drug treatments. RESULTS: BLU667- and LOXO292-tolerated persisters were cellularly heterogeneous, contained slowly proliferating cells, regained low levels of active ERK1/2, and displayed plasticity in growth rate, which we designated as in the transition state of resistance (TSR). TSR cells were genetically heterogeneous. Aurora A/B kinases were among the most significantly upregulated genes and that the MAPK pathway activity had significantly higher transcript footprints. MEK1/2 and Aurora kinase inhibitors were the most effective drugs when combined with a RET kinase inhibitor. In a TSR tumor model, combination of BLU667 with an Aurora kinase or a MEK1/2 kinase inhibitor caused TSR tumor regression. CONCLUSION: Our experiments reveal that the heterogeneous TSR cancer cells under continuous RET TKI treatment converge on the targetable ERK1/2-driven Aurora A/B kinases. The discovery of the targetable convergent point in the genetically heterogeneous TSR points to an effective combination therapy approach to eliminate the residual tumors.

Identification of polypharmacological anticancerous molecules against Aurora kinase family of proteins.

The Human Aurora Kinase (AURK) protein family is the key player of cell cycle events including spindle assembly, kinetochore formation, chromosomal segregation, centrosome separation, microtubule dynamics, and cytokinesis. Their aberrant expression has been extensively linked with chromosomal instability in addition to derangement of multiple tumor suppressors and oncoprotein regulated pathways. Therefore, the AURK family of kinases is a promising target for the treatment of various types of cancer. Over the past few decades, several potential inhibitors of AURK proteins have been identified and have reached various phases of clinical trials. But very few molecules have currently crossed the safety criteria due to their various toxic side effects. In the present study, we have adopted a computational polypharmacological strategy and identified four novel molecules that can target all three AURKs. These molecules were further investigated for their binding stabilities at the ATP binding pocket using molecular dynamics based simulation studies. The molecules selected adopting a multipronged computational approach can be considered as potential AURKs inhibitors for cancer therapeutics.

Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB.

Platinum-based chemotherapy is currently a standard treatment strategy for patients with gastric cancer. Eventhough it has been widely shown that microRNAs (miRNAs) are involved in tumor development, whether miRNAs have a role in chemosensitivity of gastric cancer cells to platinum-based treatment remain largely undefined. In this study, a cisplatin-resistant gastric cancer cell line (SGC7901/DDP) with stable enhanced expression or knockdown of let-7b was generated. MTT and TUNEL assays were carried out to assess whether miR-let-7 is crucial for cell viability and apoptosis, respectively. In vitro luciferase reporter assay was performed to explore target genes of let-7b. Further, a subcutaneously transplanted tumor model in BALB/c nude mice was used to determine the impacts of let-7b on tumor growth in vivo. We observed that the let-7b-expression level of SGC7901/DDP cells was significantly lower than for its parental SGC7901 cells. Transfection of let-7b mimics was found to increase the cytotoxicity of DDP to SGC7901/DDP cells by inducing apoptosis. However, reversed cytotoxicity of DDP was observed in SGC7901/DDP cells with knockdown of let-7b. Luciferase reporter assay indicated that let-7b targeted AURKB in SGC7901/DDP cells. Knockdown of AURKB imitated the effect of let-7b overexpression on the sensitivity of SGC7901/DDP cells to DDP. Further investigation demonstrated that the SGC7901/DDP primary tumor growth was significantly reduced by let-7b mimic transfection. These findings indicate that overexpression of let-7b might provide a potential strategic approach for attenuating DDP resistance in SGC7901/DDP human gastric cancer cells.