Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Richters, André; Doyle, Shelby K.; Freeman, David B.; Lee, Christina; Leifer, Becky; Jagannathan, Srinivasan; Kabinger, Florian; Koren, Jošt Vrabič; Struntz, Nicholas B.; Urgiles, Julie; Stagg, Ryan A.; Curtin, Brice H.; Chatterjee, Deep; Mathea, Sebastian; Mikochik, Peter J.; Hopkins, Tamara D.; Gao, Hua; Branch, Jonathan R.; Xin, Hong; Westover, Lori; Bignan, Gilles; Rupnow, Brent; Karlin, Kristen L.; Olson, Calla; Westbrook, Thomas F.; Vacca, Joseph P.; Wilfong, Chris M.; Trotter, B. Wesley; Saffran, Douglas C.; Bischofberger, Norbert; Knapp, Stefan; Russo, Joshua W.; Hickson, Ian; Bischoff, James R.; Gottardis, Marco M.; Balk, Steven P.; Lin, Charles Y.; Pop, Marius; Koehler, Angela N.

doi:10.1016/j.chembiol.2020.10.001

Cited by 55 publications

(87 citation statements)

References 79 publications

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“…The most novel ultra-selective CDK9 inhibitor KB-0742, an orally bioavailable inhibitor, has displayed great antitumor potential in pre-clinical investigation [ 760 ]. The remarkable results from KB-0742 have led to clinical trials investigating relapsed and refractory solid tumors, and non-Hodgkin lymphoma [NCT04718675].…”

Section: Myc Inhibitorsmentioning

confidence: 99%

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

et al. 2021

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MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.

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Section: Myc Inhibitorsmentioning

confidence: 99%

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

et al. 2021

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“…Previous studies reported that activity of CDK9 was involved in maintaining a high expression level of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4 [ 34 ]. Moreover, CDK9 is a promising prognostic marker and therapeutic target in cancers [ 35 ], including activity castration-resistant prostate cancers (CRPCs) models [ 36 ]. Other studies have shown a therapeutic benefit of combined cisplatin with a CDK9 inhibition, which could be particularly potent in dNER tumors [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches

Wei

Dai

Zhang

et al. 2021

IJMS

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Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.

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“…As mentioned above, these inhibitors are particularly effective in cancers that are driven by oncogenic transcription factors. For instance, inhibition of CDK9 was recently shown to repress the AR‐driven oncogenic programme in castration‐resistant prostate cancer cells in vitro and in vivo [ 176 ]. Likewise, inhibition of CDK12 resulted in synthetic lethality in Ewing sarcomas driven by the oncogenic fusion protein EWS‐FLI1 [ 177 ], which encodes for a powerful transcription factor that reprogrammes the transcriptome of sarcoma cells [ 178 ].…”

Section: Inhibition Of Splicing Factor Kinases: Emerging Therapeutic Opportunitiesmentioning

confidence: 99%

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

2021

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Alternative splicing and polyadenylation represent two major steps in pre-mRNA processing, which ensure proper gene expression and diversification of human transcriptomes. Deregulation of these processes concurs to oncogenic programs involved in onset, progression and evolution of human cancers, which often result in acquisition of resistance to existing therapies. On the other hand, cancer cells frequently increase their transcriptional rate and develop a transcriptional addiction, which imposes a high stress on the pre-mRNA processing machinery and establishes a therapeutically exploitable vulnerability. A prominent role in fine-tuning pre-mRNA processing mechanisms is played by three main families of protein kinases: SRPK, CLK and CDK. These kinases phosphorylate the RNA polymerase, splicing factors and regulatory proteins involved in cleavage and polyadenylation of the nascent transcripts. The activity of SRPKs, CLKs and CDKs can be altered in cancer cells and their inhibition was shown to exert anticancer effects. In this review, we describe key findings that have been reported on these topics and discuss challenges and opportunities of developing therapeutic approaches targeting splicing factor kinases.

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Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Cited by 55 publications

References 79 publications

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

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