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

Liu, Jinghui; Zhao, Yue; He, Daheng; Jones, Katelyn; Tang, Shan; Allison, Derek B.; Zhang, Yanquan; Chen, Jing; Zhang, Qiongsi; Wang, Xinyi; Li, Chaohao; Wang, Chi; Li, Lang; Liu, Xiaoqi

doi:10.1016/j.xcrm.2023.101015

Cited by 5 publications

(1 citation statement)

References 57 publications

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“…Another CRISPRko screen performed with enzalutamide in the C4 prostate cancer cell line demonstrated that IP6K2 knockout increased resistance, whereas XPO4 knockout had the opposite effect [142]. A CRISPRko screen to understand enzalutamide resistance in prostate cancer CWR-R1 and 22Rv1 cells and focusing on kinases revealed the role of activated BRAF [143] and of CK1α [144]. Importantly, the role of CK1α was confirmed in the LuCaP35CR and LuCaP77CR PDX prostate cancer models.…”

Section: Crispr/cas9 Knockout Screens To Identify Genes and Pathways ...mentioning

confidence: 98%

Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review

Dziubańska-Kusibab,

Nevedomskaya,

Haendler

2024

IJMS

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The advent of targeted therapies has led to tremendous improvements in treatment options and their outcomes in the field of oncology. Yet, many cancers outsmart precision drugs by developing on-target or off-target resistance mechanisms. Gaining the ability to resist treatment is the rule rather than the exception in tumors, and it remains a major healthcare challenge to achieve long-lasting remission in most cancer patients. Here, we discuss emerging strategies that take advantage of innovative high-throughput screening technologies to anticipate on- and off-target resistance mechanisms before they occur in treated cancer patients. We divide the methods into non-systematic approaches, such as random mutagenesis or long-term drug treatment, and systematic approaches, relying on the clustered regularly interspaced short palindromic repeats (CRISPR) system, saturated mutagenesis, or computational methods. All these new developments, especially genome-wide CRISPR-based screening platforms, have significantly accelerated the processes for identification of the mechanisms responsible for cancer drug resistance and opened up new avenues for future treatments.

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Section: Crispr/cas9 Knockout Screens To Identify Genes and Pathways ...mentioning

confidence: 98%

Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review

Dziubańska-Kusibab,

Nevedomskaya,

Haendler

2024

IJMS

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Development of Oral, Potent, and Selective CK1α Degraders for AML Therapy

Huang,

Chen,

Chen

et al. 2024

JACS Au

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Molecular glue degraders (MGDs) are proximityinducing agents that mediate the cooperative interaction between a target protein and an E3 ligase, introducing an additional layer of specificity beyond that afforded by traditional small molecules. Historically, molecular glues that stabilize protein−protein interactions were often discovered serendipitously. In this study, we leveraged the reprogramming potential of cereblon (CRBN)based ligands and conducted a CRBN-dependent proliferation screen to identify CRBN-based MGDs capable of inducing the degradation of proteins essential for cell viability. Through our screening and subsequent medicinal chemistry optimization, we identified dCK1α-1 as a potent and selective CK1α-targeting molecular glue degrader. Furthermore, we synthesized an orally active derivative, dCK1α-2, with enhanced pharmacokinetic properties, which exhibited pronounced degradation activity and demonstrated efficacy in mouse models following oral gavage. These findings indicate that phenotypic drug discovery campaigns, in combination with chemically distinct CRBN ligand libraries, can accelerate the development of therapeutically relevant MGDs. Furthermore, the development of dCK1α-1 and dCK1α-2 provides new therapeutic options for cancers with functional p53 signaling and offers valuable chemical tools for future investigations into the role of CK1α.

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Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling

Li,

Ning,

Zhao

et al. 2023

Cancer Research

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The next-generation androgen receptor (AR) inhibitor enzalutamide (ENZ) is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome ENZ resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of ENZ-resistant prostate cancer cells to ENZ both in vivo and in vitro. Inhibition of PGAM2 together with ENZ treatment triggered apoptosis by decreasing levels of the anti-apoptotic protein BCL-xL and increasing activity of the pro-apoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to ENZ-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of ENZ resistance in prostate cancer patients. Together, these findings provide evidence of a non-metabolic function of PGAM2 in promoting ENZ resistance and identify PGAM2 inhibition as a promising therapeutic strategy for ENZ-resistant prostate cancer.

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

Cited by 5 publications

References 57 publications

Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review

Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review

Development of Oral, Potent, and Selective CK1α Degraders for AML Therapy

Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling

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