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Treatment of prostate cancer cell lines with Androgen Receptor and Receptor Tyrosine Kinase inhibitors

ABSTRACT: Treatment of prostate cancer cell lines with Androgen Receptor and Receptor Tyrosine Kinase inhibitors

PROVIDER: PRJNA918580 | ENA |

REPOSITORIES: ENA

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Treatment of prostate cancer cell lines with Androgen Receptor and Receptor Tyrosine Kinase inhibitors

Project description:Androgen receptor (AR)-targeted therapy is the mainstay of systemic treatments for recurrent and metastastic prostate cancer given the tumor cell's dependency on testosterone signaling for growth and survival. However, numerous bypass pathways have been nominated that may circumvent AR in the context of AR-targeted therapies. In this project, we tested whether AR and receptor tyrosine kinase (RTK) activity opposed each other and if inhibition of one promoted the activation of another. We assessed the impact of AR or RTK inhibition in three prostate cancer cell lines over a 5-day time course. We then performed paired-end RNA-seq to assess differential gene expression. Our findings suggest that the AR and HER2 pathways dynamically interact with each other at the transcriptional level.

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Novel Eph receptor tyrosine kinase inhibitors block colorectal cancer cell growth

Project description:Despite advances, treatment of unresectable colorectal cancer remains a clinical challenge and the incidence of this malignancy is increasing in individuals below the age of fifty. Integrated genomic, transcriptomic, proteomic, and mechanistic studies identified the tyrosine kinase receptors EphB2 and EphB4 as colorectal cancer drivers, and EphA2 activity as a cancer resistance mechanism to epidermal growth factor receptor and BRAF inhibitors. Reduction of EphB2 and EphB4 activity suppresses colorectal cancer cell growth and survival and is a potential target for colorectal cancer therapy. Here, we report the design and synthesis of two novel inhibitors, 1 and 3, that selectively bind with high affinity to A and B-type Eph receptor tyrosine kinases, inhibit A and B-type Eph tyrosine kinase activity, induce cell cycle arrest and confer a protracted state of growth reduction to colorectal cancer cells. 1 and 3 bind to EphA2 arresting the activation loop containing the conserved Asp-Phe-Gly (“DFG”)-motif in an inactive conformation and show a conserved hydrogen bond interaction with the so-called gatekeeper residue, the activation loop, alphaC helix, and hinge region of the kinase, typical of kinase inhibitors. These results demonstrate that pharmacological inhibition of Eph tyrosine kinase receptors is a valid therapeutic approach for the treatment of colorectal cancer.

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Host-dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors

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Tumor-independent host gene expression changes induced by tyrosine kinase inhibitors

Project description:Transcriptome analysis was used to identify tumor-independent changes after treatment with different tyrosine kinase inhibitors (TKIs).

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Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

Project description:Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells. It is a target of tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment. Flt3 and its ligand (Flt3L) are expressed in the heart and cardiac side effects occur under Flt3-targeting TKIs. Whether Flt3/Flt3L also regulate cardiac progenitor cells (CPCs), however, is not known. The cardiac side population (SP) is a pool of heterogenous CPCs that can give rise to all cardiac lineages, hence contributing to cardiovascular homeostasis. Here we show that SP-CPCs produce and are responsive to Flt3L. Compared to wild-type, SP-CPCs from flt3L-/- mice are less abundant, with less contribution of CD45-CD34+ cells, and lower expression of gene sets related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing and compared to wild-type, flt3L-/- Sca1+CD31- SP-CPCs show increased proliferation and less vasculogenic commitment, but differentiation can be induced in the presence of receptor tyrosine kinase-activating growth factors. The observed differences are associated with decreased microvascularisation and global systolic function of flt3L-/- hearts. Thus, Flt3 contributes to a receptor tyrosine kinase signature necessary for the maintenance and functionality of SP-CPCs. These findings have potential implications regarding cardiovascular side effects observed under TKI therapy.

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Receptor Tyrosine Kinase Inhibitors Block proliferation of coronavirus mainly through p38 mitogen-activated protein kinase pathways

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