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Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus

ABSTRACT: Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora kinase A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer (BC) cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors that exhibited 10-fold improved oral bioavailability. DBPR728 induced persistent tumor regression of c-MYC- and/or N-MYC- overexpressing xenografts including SCLC, triple-negative breast cancer (TNBC), hepatocellular carcinoma and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor elimination half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC cancers. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242151 | GEO | 2023/09/18

REPOSITORIES: GEO

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Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Castration Resistant and Neuroendocrine Prostate Cancer

Project description:<p>Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. In this single arm, multi-institutional open label phase 2 clinical trial of alisertib, sixty men were treated with alisertib 50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival. Pre-treatment biopsies were evaluated by whole exome and RNA-seq.</p>

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Next Generation Sequencing was performed on MDSCs from tumors of control or alisertib treated tumor-bearing mice

Project description:The Aurora-A inhibitor alisertib shows encouraging activities in clinical trials against multiple malignances including advanced breast cancer. However, its mechanism of action remains unclear, especially regarding how the inflammatory microenvironment is involved in the efficacy of alisertib. Here, we demonstrated that Aurora-A inhibition directly reshapes the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anti-cancer T lymphocytes, which restores a tumor-suppressive microenvironment and significantly contributes to the regression of murine mammary tumors. Mechanistically, the Aurora-A inhibitor effectively eliminated myeloid cells including myeloid-derived suppressor cells (MDSCs) and macrophages in tumors by triggering apoptosis of these cells. Further, Aurora-A inhibition could disrupt the immunosuppressive functions of MDSCs through inhibiting Stat3 mediated ROS production. These alterations led to significant increases in the proportion and the number of CD8+ and CD4+ T lymphocytes, which efficiently inhibited the proliferation of tumor cells. In summary, these data revealed that in addition to suppressing the proliferation of tumor cells, Aurora-A inhibitor directly modulates and restores an anti-tumor immune-microenvironment in breast cancer. Intriguingly, Aurora-A inactivation combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors, providing an effective strategy for clinical trials of chemo-immunotherapy in breast cancer.

2021-10-21 | GSE121570 | GEO

Comparison of gene expression patterns of two SCLC genetically-engineered mouse models; Rb1 floxed, Trp53 floxed, LSL-Myc T58A-IRES-Luc vs. Rb1 floxed, Trp53 floxed, Rbl2 (p130) floxed

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2017-01-12 | GSE89660 | GEO

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

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Simultaneous silencing of Aurora-A and UHRF1 inhibits colorectal cancer cell growth by regulating the expression of DNMT1 and STAT1

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2020-10-26 | GSE160037 | GEO

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

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2023-12-27 | PXD043444 | Pride

RNA seq_A375 gSMARCB1 + A549 etoposide, Aurora kinases inhibitors treated

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2017-09-21 | GSE102639 | GEO

Transcription profiling of human xenograft laboratory models and primary tumors of small cell lung cancer

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Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer

Project description:A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.

2024-01-26 | PXD029972 | Pride

Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer (batch2-6)

2024-01-26 | PXD029968 | Pride

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