Project description:Oral selective estrogen receptor degraders (SERDs) could become the backbone endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. This dataset was aimed at exploring the preclinical effects of the next-generation oral SERD camizestrant (AZD9833) on 7 PDX models. Mice were treated with fulvestrant or camizestrant for 4, 24, 48, 72 hours, with at least four replicates per condition.
Project description:Acquired resistance to tamoxifen and fulvestrant is a challenging clinical problem in the treatment of hormone receptor-positive breast cancer patients. Non-coding RNAs (ncRNAs) could contribute to endocrine resistance but their specific roles in tamoxifen and fulvestrant resistance are not fully understood.
Project description:Acquired resistance to tamoxifen and fulvestrant is a challenging clinical problem in the treatment of hormone receptor-positive breast cancer patients. Non-coding RNAs (ncRNAs) could contribute to endocrine resistance but their specific roles in tamoxifen and fulvestrant resistance are not fully understood.
Project description:Acquired resistance to tamoxifen and fulvestrant is a challenging clinical problem in the treatment of hormone receptor-positive breast cancer patients. Non-coding RNAs (ncRNAs) could contribute to endocrine resistance but their specific roles in tamoxifen and fulvestrant resistance are not fully understood.
Project description:Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are being investigated in combination with different endocrine treatments. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined. Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant. Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. High CDK6 levels in metastatic samples from breast cancer patients treated with fulvestrant (N=45) correlated significantly with shorter progression-free survival (PFS) (p=0.0006), while no association was observed in patients receiving other endocrine treatments (N=41, p=0.874). Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample
Project description:Activation of the PI3K pathway in estrogen receptor α (ER)-positive (+) breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. PTEN is a negative regulator of the PI3K pathway typically lost in ER-negative (-) breast cancer. To clarify the effect of PTEN down-regulation on the response of ER+/HER2- breast cancer to endocrine therapy, we established reduced PTEN cell models using inducible knockdown. We found that only moderate PTEN reduction is sufficient to enhance PI3K signaling, generate a gene signature associated with luminal B subtype, and cause endocrine resistance. Combining endocrine therapy with mTOR, AKT, or MEK inhibitors improves antitumor activity, but the efficacy varies by type of endocrine therapy and the specific inhibitor. Fulvestrant plus an AKT inhibitor is the most potent combination when PTEN is reduced, inducing apoptosis and tumor regression. This combination deserves further study in patients with PI3K pathway activation.
Project description:The PI3Kalpha-specific inhibitor Alpelisib (BYL719) has been approved for the treatment of metastatic ER+/HER2- breast cancer patients in combination with Fulvestrant. After initial response, patients develop drug resistance and disease relapses. In order to identify signalling pathways contributing to the acquired resistance to BYL719 in breast cancer, we generated BYL719-resistant T47D cells and used them together with the parental cells to perform label-free quantitative phosphoproteomics.
Project description:Here we characterise the response of models of ER-positive breast cancer to treatment with the small molecule MDM2 inhibitor NVP-CGM097, a dihydroisoquinolinone derivative currently evaluated in a phase I clinical trial. We show that NVP-CGM097 reduces tumour cell viability of in vitro and in vivo models of endocrine sensitive, endocrine resistant and palbociclib (CDK4/6 inhibitor) resistant p53 wildtype (p53wt) ER-positive breast cancer. NVP-CGM097 synergises with both fulvestrant and palbociclib in models of therapy resistance. Importantly, we identify the key mechanisms of the synergistic interactions between NVP-CGM097 and endocrine therapy, which occurs through the inhibition of E2F Targets and G2M Checkpoint signalling and induction of senescence, rather than depending upon upregulation of p53 dependent apoptotic pathways. Moreover, we find these same pathways are synergistically targeted during the combination treatment of ER positive breast cancer models with NVP-CGM097 and palbociclib. This indicates the genuine potential of MDM2 inhibition as therapy in advanced ER-positive breast cancer as combination endocrine therapy and CDK4/6 inhibitor treatment becomes embedded as standard of care.
Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.