Reference Detail

Ref Type

Journal Article

PMID

(36129942)

Authors

Sun R, Wei T, Ding D, Zhang J, Chen S, He HH, Wang L, Huang H

Title

CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	119	39	2022 09 27	e2205509119	Proc Natl Acad Sci U S A

URL

Abstract Text

Androgen receptor (AR) messenger RNA (mRNA) alternative splicing variants (AR-Vs) are implicated in castration-resistant progression of prostate cancer (PCa), although the molecular mechanism underlying the genesis of AR-Vs remains poorly understood. The CDK12 gene is often deleted or mutated in PCa and CDK12 deficiency is known to cause homologous recombination repair gene alteration or BRCAness via alternative polyadenylation (APA). Here, we demonstrate that pharmacological inhibition or genetic inactivation of CDK12 induces AR gene intronic (intron 3) polyadenylation (IPA) usage, AR-V expression, and PCa cell resistance to the antiandrogen enzalutamide (ENZ). We further show that AR binds to the CCNK gene promoter and up-regulates CYCLIN K expression. In contrast, ENZ decreases AR occupancy at the CCNK gene promoter and suppresses CYCLIN K expression. Similar to the effect of the CDK12 inhibitor, CYCLIN K degrader or ENZ treatment promotes AR gene IPA usage, AR-V expression, and ENZ-resistant growth of PCa cells. Importantly, we show that targeting BRCAness induced by CYCLIN K down-regulation with the PARP inhibitor overcomes ENZ resistance. Our findings identify CYCLIN K down-regulation as a key driver of IPA usage, hormonal therapy-induced AR-V expression, and castration resistance in PCa. These results suggest that hormonal therapy-induced AR-V expression and therapy resistance are vulnerable to PARP inhibitor treatment.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
CDK12	G909E	missense	unknown	CDK12 G909E lies within the protein kinase domain of the Cdk12 protein (PMID: 22512864). G909E results in increased androgen receptor activation compared to wild-type Cdk12 and is associated with resistance to anti-androgen therapy in cultured cells (PMID: 36129942), but has not been fully biochemically characterized and therefore, its effect on Cdk12 protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDK12 G909R	prostate cancer	predicted - resistant	Enzalutamide	Preclinical - Cell culture	Actionable	In a preclinical study, expression of CDK12 G909R in prostate cancer cells was associated with increased growth in the presence of Xtandi (enzalutamide) in culture (PMID: 36129942).	36129942
CDK12 G909E	prostate cancer	predicted - resistant	Enzalutamide	Preclinical - Cell culture	Actionable	In a preclinical study, expression of CDK12 G909E in prostate cancer cells was associated with increased growth in the presence of Xtandi (enzalutamide) in culture (PMID: 36129942).	36129942