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Inhibition of CK1e potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

ABSTRACT: In this study, we found that combination treatment of breast cells with CK1 inihbitor (D 4476) and CDK4/6 inhibitor (Ribociclib) exhibited greatly enhanced therapeutic efficacy than CDK4/6 inhiitor single treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE177054 | GEO | 2021/08/10

REPOSITORIES: GEO

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Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.

Project description:Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

| S-EPMC8433397 | biostudies-literature

Inhibition of CK1e potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Project description:Inhibition of CK1e potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

| PRJNA736983 | ENA

MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance (miRNA-Seq)

Project description:CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor (ER)-positive breast cancer, so that defining mechanisms of resistance is a pressing issue. Here, we identify increased CDK6 expression as a key determinant of acquired resistance after exposure to palbociclib in ER-positive breast cancer cells. Increased CDK6 in resistant cells was dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediated transfer of the resistance phenotype between neighboring cell populations. We confirmed these data in pre-treatment and post-progression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating clinical relevance of this mechanism. Additionally, the CDK4/6 inhibitor resistance phenotype can be reversed in vitro and in vivo by a prolonged drug holiday.

2019-03-04 | GSE117747 | GEO

MicroRNA-mediated suppression of the TGF-ß pathway confers transmissible and reversible CDK4/6 inhibitor resistance (miRNA array)

2019-03-04 | GSE117745 | GEO

MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance (array II)

2019-03-04 | GSE117743 | GEO

MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance (array I)

2019-03-04 | GSE117742 | GEO

MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance (RNA-Seq)

2019-03-04 | GSE117746 | GEO

PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in metastatic cancer

Project description:We performed single-cell RNA-sequencing and T-cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We identified evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation.

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Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model. In order to generate DIPG‐bearing mice, we are using the RCAS/Tv‐a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells‐of‐origin using transgenic Tv‐a‐expressing mice (Tv‐a being the receptor for RCAS viruses). We injected P3‐P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS‐PDGF‐A + RCAS‐H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy.

2021-09-28 | GSE184786 | GEO

Cdk4-inhibitor induces tumor regression of Bladder cancer in vivo

Project description:Cdk4/6 inhibitors have shown to increase overall survival in hormone-positive breast tumors, but whether other solid tumors could respond to these inhibitors has not yet defined. Here we show that Palbociclib (a Cdk4/6 specific inhibitor in clinic use) treatment exerts antiproliferative effects in vivo using a bladder cancer cell lines.

2018-10-22 | GSE105402 | GEO

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