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A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199539 | GEO | 2022/03/30

REPOSITORIES: GEO

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A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer.

Project description:Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance. PRRX2 expression was the highest in double-negative prostate cancer (DNPC), which lack AR signaling and neuroendocrine differentiation, and a PRRX2-related gene signature identified a subset of patients with DNPC with reduced overall survival. PRRX2-expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, treatment with CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing, castration-resistant tumors to enzalutamide. Overall, PRRX2 was identified as a driver of enzalutamide resistance. The PRRX2 signature merits investigation as a biomarker of enzalutamide resistance in prostate cancer that could be reversed with CDK4/6 and BCL2 inhibitors.SignificancePRRX2 mediates enzalutamide resistance via activation of the E2F and BCL2 pathways, which can be targeted with CDK4/6 and BCL2 inhibitors to reverse resistance.

| S-EPMC9177667 | biostudies-literature

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

Project description:We report that PRRX2 mediates enzalutamide resistance by activating the anti-apoptotic BCL2 and theE2F/RB1 cell cycle pathways.

2022-03-30 | GSE199538 | GEO

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

Project description:We report that PRRX2 mediates enzalutamide resistance by activating the anti-apoptotic BCL2 and theE2F/RB1 cell cycle pathways.

2022-03-30 | GSE199537 | GEO

A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer.

Project description:Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

| S-EPMC10140619 | biostudies-literature

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

| PRJNA820694 | ENA

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

| PRJNA820699 | ENA

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

| PRJNA820696 | ENA

Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation.

Project description:Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49B-Rac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.

| S-EPMC5924929 | biostudies-literature

A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer.

Project description:Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.

| S-EPMC8249522 | biostudies-literature

A kinome-wide CRISPR screen identifies CK1α as a novel target to overcome enzalutamide resistance of prostate cancer

Project description:Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1 alpha (CK1α) as a novel therapeutic target to overcome enzalutamide resistance. To dissect the underlying mechanisms of targeting CK1α to sensitize cancer cells to ENZA, we performed RNA sequencing of 22Rv1 cells upon CK1α knockout or overexpression. We found that CK1α regulated double-strand break (DSB)-response signaling.

2023-03-10 | GSE203362 | GEO

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