Project description:T47D and MCF7 cell lines were treated with long-term (continuous) palbociclib to induce 4 resistant cell-lines (T47D RB-, T47D CDK6H, MCF7 RB- and MCF7 PacqR). Each cell line (both parental and resistant) were then treated with DMSO (control), capivasertib monotherapy, fulvestrant monotherapy and capivasertib/fulvestrant combination. RNA data is available after each treatment and resistant cell lines additionally have RNA data available after continuous palbociclib treatment.
Project description:Myelofibrosis (MF) is a deadly blood neoplasia that presents the worst prognosis among myeloproliferative neoplasms (MPN). Expression of CDK6 is significantly elevated in MPN/MF hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor Palbociclib alone or in combination with Ruxolitinib in Jak2V617F and MPLW515L murine models of MF. Treatment of Palbociclib alone significantly reduced leukocytosis, splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of Palbociclib and Ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size and abrogation of bone marrow fibrosis in murine models of MF. Mechanistically, we show that Palbociclib treatment or depletion of CDK6 inhibits Aurora kinase, NF-κB and TGF-β signaling pathways in Jak2V617F mutant hematopoietic cells. Overall, our data suggest that Palbociclib in combination with Ruxolitinib may have therapeutic potential for treatment of MF.
Project description:This early phase I trial studies the direct effects on cancer cells of the drugs binimetinib and palbociclib, in patients with KRAS-positive lung, colorectal, or pancreatic cancer that can be removed by surgery (operable). Binimetinib and palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving binimetinib and palbociclib may halt the growth of cancer cells and improve access of the immune system cells, a patient’s own cells that fight infection and cancer, into the tumor.
Project description:The results from our study have identified two clinically relevant, divergent and druggable pathways (DNA repair and STAT3) that can be targeted in combination to effectively combat drug resistance. We also found that the same pathways that were deregulated in palbociclib-resistant cells were also altered in tumor samples obtained from patients who progressed while on palbociclib and endocrine therapy
Project description:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.
Project description:We evaluated the TGFβ blocking antibody NIS793 in combination with either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX chemotherapy in orthotopic pancreatic cancer. Blockade of TGFβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. TGFβ blockade decreased total aSMA+ fibroblasts but had minimal effect on fibroblast heterogeneity.
Project description:We examined differential gene expression profiles between MCF7 human breast cancer cells treated with vehicle alone (control), palbociclib monotherapy, palbociclib alternating with ICI182,780 treatment, and palbociclib resistant cells. For this, we used gene microarray expression profiling to identify significantly changed genes under different treatment conditions.
Project description:Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in established MPM cell lines using a variety of approaches including RNA sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 4 of 6 cell lines. In a parallel study, the efficacy of palbociclib was confirmed in a large panel of patient-derived cell lines indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4, which was associated with the high p16 levels that accompany RB1 defects or inactivation, and also (unexpectely) CCNE1 overexpression in the presence of WT RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype (SASP) including various potentially immunogenic components was also irreversibly induced. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment including in several combinatorial therapies.