Effect of Sulfopin and Abemaciclib treatment on gene expression in mouse TNBC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232422 | GEO | 2024/03/08
REPOSITORIES: GEO
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Project description:Effect of Sulfopin and Abemaciclib treatment on gene expression in mouse TNBC
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Project description:The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1’s active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Still, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.
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Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
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Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
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Project description:Current research on CDK4/6 inhibitors (CDK4/6i) in the pre-clinical and clinical spaces are largely concerned with gaining a deeper understanding of how these drugs delay tumor growth, and how to prevent cancer cell resistance. By coordinating a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies to identify the molecular basis of geroconversion, we have defined how therapy induced senescence contributes to disease management. Thirty patients with progressing DDLS enrolled in the clinical trial and were treated with 200mg abemaciclib twice daily. The median progression free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI 57.7% - 90.1%). ANGPTL4 is a necessary late regulator of geroconversion, the pathway from reversible cell cycle exit to a stably arrested inflammation-provoking senescent cell, in liposarcoma cell lines treated with CDK4/6i. Using ANGPTL4 and CDKN2A expression, we were able to identify patients in which abemaciclib induced tumor cell senescence. We were then able to correlate this with outcomes. Senesence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy, and possibly with an improved initial response to abemaciclib. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance after six months of therapy. This suggests that combining senolytics with abemaciclib in a subset of patients may improve the durability of patient responses to this class of compounds.
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Project description:The cellular and organismal phenotypic response to a small molecule kinase inhibitor is defined collectively by the inhibitor’s targets and their functions. The selectively of small molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based approach to define the target landscape of kinase inhibitors. Here we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib, and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3 and GSK3 were the most potently inhibited. Cell based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits (GSK3/β) kinase activity at low nanomolar concentrations. Consequently, abemaciclib activates β-catenin-dependent WNT signaling, as determined by β-catenin transcriptional activation and β-catenin protein stabilization. These data reveal differential kinase target specificities for CDK4/6 inhibitors may help explain differential clinical efficacy and dose-limiting toxicities. More broadly, we highlight the power of competitive chemical proteomics to identify multiple targets of kinase inhibitors in protein lysate, treated cells and in treated mice.
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Project description:Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC.
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Project description:Sulfopin, a covalent inhibitor of Pin1, blocks Myc-driven tumors in vivo
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