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Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

ABSTRACT: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression.We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer.Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal-regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels.These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells.

SUBMITTER: Eggers JP

PROVIDER: S-EPMC3425449 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

Eggers John P JP Grandgenett Paul M PM Collisson Eric C EC Lewallen Michelle E ME Tremayne Jarrod J Singh Pankaj K PK Swanson Benjamin J BJ Andersen Judy M JM Caffrey Thomas C TC High Robin R RR Ouellette Michel M Hollingsworth Michael A MA

Clinical cancer research : an official journal of the American Association for Cancer Research 20110808 19

<h4>Purpose</h4>To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression.<h4>Experimental design</h4>We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer.<h4>Results</h4>Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarc ...[more]

PMID: 21825040

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Project description:BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n?=?172) or circulating tumor DNA (n?=?145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median?=?34.9 mo, p?=? 0.004) and development of castration-resistant disease (median = 32.7 mo, p?<? 0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p?=? 0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.ConclusionsOur data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.Patient summaryIn this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ?8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.

Dataset Information

Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

Publications

Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

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