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[This corrects the article DOI: 10.3389/fphar.2024.1361424.].

Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches.

Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC. [Display omitted] Huang, Lin, and colleagues show that long noncoding RNA HOXD-AS1 is upregulated in castration-resistant prostate cancer (CRPC) and correlated with disease progression. HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance of prostate cancer cells via interacting with WDR5, which in turn activates the transcription of downstream genes.

Yuan C, Zhou Z, Yang Y, et al. Drug Des Devel Ther. 2015;9:487–508. We, the Editors and Publisher of the journal Drug Design, Development and Therapy, have retracted the published article. After publication, concerns were raised by a third party regarding the integrity of the data in Figure 5, Figure 7 and Figure 11 of the article. Further investigations conducted by the Journal and Publisher confirmed the following: Figure 5 includes duplicate image panels between samples representative of different experimental conditions; Unexpected similarities have been identified in the Western blot data shown in Figures 5a and 7a of the above article, and Figure 4a of the authors’ published article, which represent different experimental conditions. Both articles were submitted contemporaneously: Yuan C, Zhou Z, Yang Y, et al. Danusertib, a potent pan-Aurora kinase and ABL kinase inhibitor, induces cell cycle arrest and programmed cell death and inhibits epithelial to mesenchymal transition involving the PI3K/Akt/mTOR-mediated signaling pathway in human gastric cancer AGS and NCI-N78 cells. Drug Des Devel Ther. 2015;9:1293–1318. https://doi.org/10.2147/DDDT.S74964 When approached for an explanation, the authors checked their data and confirmed there are fundamental errors present. Therefore, they have agreed to the retraction of this article. The authors apologize for this oversight. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Aurora kinase A (AURKA) is aberrantly expressed in a large number of tumors and promotes tumor progression by regulating the cell cycle, chromosomal instability, and drug resistance. However, its heterogeneous expression and combination therapy benefit in prostate adenocarcinoma (PRAD) is unclear. In this study, we integrated TCGA pan-cancer multi-omics data and GEO data to analyze the RNA, methylation, protein expression, and genomic alteration characteristics of AURKA. We then used single-cell RNA sequencing to resolve the functional heterogeneity of AURKA in the PRAD epithelial cell subpopulation and verified its impact on the malignant phenotype of desmoplasia-resistant prostate cancer cells in in vitro experiments. This research also analyzed the prognostic risk stratification of AURKA subpopulations in combination with various indicators and the potential benefit of AURKA inhibitors in combination with various treatments. The pan-cancer analysis demonstrated that AURKA expression heterogeneity was present among urological tumors at different molecular levels, and the positive correlation of AURKA alteration with MYC and E2F pathways was conserved in pan-cancer. Epithelial cell subpopulations with high expression of AURKA (epi3/4/6) promoted proliferation by regulating cell cycle and DNA repair, while low expression subsets (epi1/2/7) activated TNF-α and androgen receptor (AR) pathways to mediate drug resistance. In particular, AURKA may serve as a compensatory pathway to support tumor activity after AR inhibition in prostate cancer, a complex mechanism not seen in other tumors. AURKA-overexpressing patients with low Gleason scores or high PSA have a poor prognosis in clinical analysis. Furthermore, a comprehensive drug sensitivity co-analysis found that AURKA inhibitors may benefit from targeted therapy, ADC therapy, and immunotherapy. TMB and CD274 expression were the biomarkers of AURKA high-expression patients with PRAD for clinical outcome. AURKA expression heterogeneity has been identified as a critical factor in the progression of PRAD and the development of drug resistance. The molecular subtyping of AURKA can serve as a precise strategy for combination therapy and provide a theory for the combination of AURKA inhibitors and targeted/immunotherapy.

Glioblastoma (GBM) is the most common and aggressive primary adult CNS tumor. Increased understanding of glioma biology is needed for novel treatment strategies and maximization of current therapies. The action of the widely used antiglioma drug, temozolomide (TMZ), relies on its ability to methylate DNA guanine bases leading to DNA double strand breaks and apoptosis. However, glioma cells capable of reversing guanine methylation via the repair enzyme O 6 -methylguanine DNA methyltransferase (MGMT) are resistant to TMZ. GBMs exhibiting high MGMT expression, reflected by MGMT gene promoter hypomethylation, respond poorly to both chemo- and radiation therapy. To investigate possible non-canonical biological effects of MGMT and develop a tool to investigate drug sensitivity and resistance, we generated MGMT knockout (KO) U1242 GBM cells. MGMT KO U1242 cells showed substantially increased sensitivity to TMZ in vivo , and unlike wildtype U1242 cells, failed to form tumors in nude mouse brains. They also showed reduced growth in soft agar, as did wildtype U1242 and additional glioma cell lines in which MGMT expression was knocked down by siRNA. MGMT thus possesses cellular functions related to tumor cell engraftment and anchorage-independent growth beyond guanine methyltransferase repair. We additionally show that the combination of the AURKA inhibitor alisertib and carboplatin selectively induces apoptosis in high MGMT expressing wildtype U1242 cells versus MGMT KO U1242 cells and extends survival of mice orthotopically implanted with wildtype U1242 cells. This or other platinum-based drug combinations may represent a potentially effective treatment approach to chemotherapy for GBM with MGMT promoter hypomethylation.

AURKA is a serine/threonine kinase overexpressed in several cancers. Originally identified as a protein with multifaceted roles during mitosis, improvements in quantitative microscopy uncovered several non-mitotic roles as well. In physiological conditions, AURKA regulates cilia disassembly, neurite extension, cell motility, DNA replication and senescence programs. In cancer-like contexts, AURKA actively promotes DNA repair, it acts as a transcription factor, promotes cell migration and invasion, and it localises at mitochondria to regulate mitochondrial dynamics and ATP production. Here we review the non-mitotic roles of AURKA, and its partners outside of cell division. In addition, we give an insight into how structural data and quantitative fluorescence microscopy allowed to understand AURKA activation and its interaction with new substrates, highlighting future developments in fluorescence microscopy needed to better understand AURKA functions in vivo. Last, we will recapitulate the most significant AURKA inhibitors currently in clinical trials, and we will explore how the non-mitotic roles of the kinase may provide new insights to ameliorate current pharmacological strategies against AURKA overexpression.

Aurora A kinase (AURKA) is an important regulator of cell division and is required for assembly of the mitotic spindle. We recently reported the unusual finding that this mitotic kinase is also found on the sperm flagellum. To determine its requirement in spermatogenesis, we generated conditional knockout animals with deletion of the Aurka gene in either spermatogonia or spermatocytes to assess its role in mitotic and postmitotic cells, respectively. Deletion of Aurka in spermatogonia resulted in disappearance of all developing germ cells in the testis, as expected, given its vital role in mitotic cell division. Deletion of Aurka in spermatocytes reduced testis size, sperm count, and fertility, indicating disruption of meiosis or an effect on spermiogenesis in developing mice. Interestingly, deletion of Aurka in spermatocytes increased apoptosis in spermatocytes along with an increase in the percentage of sperm with abnormal morphology. Despite the increase in abnormal sperm, sperm from spermatocyte Aurka knockout mice displayed increased progressive motility. In addition, sperm lysate prepared from Aurka knockout animals had decreased protein phosphatase 1 (PP1) activity. Together, our results show that AURKA plays multiple roles in spermatogenesis, from mitotic divisions of spermatogonia to sperm morphology and motility.