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Ref Type Journal Article
PMID (12777976)
Authors Robinson WA, Miller TL, Harrold EA, Bemis LT, Brady BM, Nelson RP
Title The effect of flavopiridol on the growth of p16+ and p16- melanoma cell lines.
Journal Melanoma research
Vol 13
Issue 3
Date 2003 Jun
URL
Abstract Text Flavopiridol is the first cyclin-dependent kinase inhibitor to enter clinical trials. Flavopiridol has been shown to mimic, in part, the effect of the cell cycle control gene p16, which is frequently lost or mutated in malignant melanoma, making it an ideal candidate for targeted therapy in this disease. In these studies we investigated the effect of flavopiridol, at various concentrations, on the growth and gene expression of nine human melanoma cell lines with intact, absent or mutated p16. A cytostatic effect of flavopiridol on the growth of six melanoma cell lines with a mutated or non-expressed p16 (p16-) was seen at low concentrations of flavopiridol (mean 50% inhibitory concentration [IC(50)] = 12.5 nM), while the three melanoma cell lines with intact p16 (p16+) required higher concentrations (mean IC(50) = 25 nM) to produce this effect. Apoptotic cell death increased with increasing concentrations of flavopiridol in both p16- and p16+ cells. Exposure of cells to high flavopiridol concentrations (>100 nM) resulted in decreased expression of genes downstream in the normal p16 cell cycle control pathway (Rb and E2F) and the anti-apoptotic gene BCL2. No change in BCL2 expression was found after exposure to IC(50) concentrations of flavopiridol. These data indicate that flavopiridol in low, clinically achievable concentrations may have significant cytostatic effects, particularly in p16- melanoma cells, and may provide new molecular-based therapies for melanoma, particularly when combined with agents that target anti-apoptotic mechanisms.

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Molecular Profile Treatment Approach
CDKN2A E69* CDK Inhibitor (Pan)
CDKN2A Y44Lfs*76 CDK6 Inhibitor
CDKN2A A102fs CDK Inhibitor (Pan)
CDKN2A Q50* CDK Inhibitor (Pan)
CDKN2A C72fs CDK Inhibitor (Pan)
CDKN2A T77fs CDK6 Inhibitor
CDKN2A E88* CDK6 Inhibitor
CDKN2A Y44* CDK6 Inhibitor
CDKN2A G23fs CDK Inhibitor (Pan)
CDKN2A S56fs CDK6 Inhibitor
CDKN2A V82fs CDK Inhibitor (Pan)
CDKN2A T77fs CDK Inhibitor (Pan)
CDKN2A L16fs CDK Inhibitor (Pan)
CDKN2A T79fs CDK Inhibitor (Pan)
CDKN2A F90fs CDK Inhibitor (Pan)
CDKN2A W15* CDK Inhibitor (Pan)
CDKN2A C72fs CDK6 Inhibitor
CDKN2A E119* CDK Inhibitor (Pan)
CDKN2A Y44fs CDK Inhibitor (Pan)
CDKN2A R58* CDK6 Inhibitor
CDKN2A M52fs CDK6 Inhibitor
CDKN2A A76fs CDK Inhibitor (Pan)
CDKN2A W15fs CDK Inhibitor (Pan)
CDKN2A A68fs CDK Inhibitor (Pan)
CDKN2A A60fs CDK6 Inhibitor
CDKN2A W110* CDK6 Inhibitor
CDKN2A E120* CDK Inhibitor (Pan)
CDKN2A T79fs CDK6 Inhibitor
CDKN2A Q50fs CDK6 Inhibitor
CDKN2A L78fs CDK6 Inhibitor
CDKN2A C72* CDK Inhibitor (Pan)
CDKN2A R58* CDK Inhibitor (Pan)
CDKN2A E88* CDK Inhibitor (Pan)
CDKN2A del CDK6 Inhibitor
CDKN2A V106fs CDK Inhibitor (Pan)
CDKN2A L65fs CDK Inhibitor (Pan)
CDKN2A E33fs CDK6 Inhibitor
CDKN2A L78fs CDK Inhibitor (Pan)
CDKN2A V82fs CDK6 Inhibitor
CDKN2A R80* CDK Inhibitor (Pan)
CDKN2A E120* CDK6 Inhibitor
CDKN2A Q50fs CDK Inhibitor (Pan)
CDKN2A F90fs CDK6 Inhibitor
CDKN2A L65fs CDK6 Inhibitor
CDKN2A A68fs CDK6 Inhibitor
CDKN2A W15fs CDK6 Inhibitor
CDKN2A Y44fs CDK6 Inhibitor
CDKN2A P81fs CDK6 Inhibitor
CDKN2A W15* CDK6 Inhibitor
CDKN2A G23fs CDK6 Inhibitor
CDKN2A A102fs CDK6 Inhibitor
CDKN2A R80* CDK6 Inhibitor
CDKN2A S56fs CDK Inhibitor (Pan)
CDKN2A L16fs CDK6 Inhibitor
CDKN2A E119* CDK6 Inhibitor
CDKN2A loss CDK Inhibitor (Pan)
CDKN2A S12* CDK Inhibitor (Pan)
CDKN2A E33fs CDK Inhibitor (Pan)
CDKN2A del CDK Inhibitor (Pan)
CDKN2A loss CDK6 Inhibitor
CDKN2A A76fs CDK6 Inhibitor
CDKN2A M52fs CDK Inhibitor (Pan)
CDKN2A S12* CDK6 Inhibitor
CDKN2A P81fs CDK Inhibitor (Pan)
CDKN2A Q50* CDK6 Inhibitor
CDKN2A R58fs CDK Inhibitor (Pan)
CDKN2A W110fs CDK6 Inhibitor
CDKN2A R58fs CDK6 Inhibitor
CDKN2A Y44Lfs*76 CDK Inhibitor (Pan)
CDKN2A A60fs CDK Inhibitor (Pan)
CDKN2A E69* CDK6 Inhibitor
CDKN2A W110fs CDK Inhibitor (Pan)
CDKN2A C72* CDK6 Inhibitor
CDKN2A V106fs CDK6 Inhibitor
CDKN2A Y44* CDK Inhibitor (Pan)
CDKN2A W110* CDK Inhibitor (Pan)
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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDKN2A loss melanoma sensitive Alvocidib Preclinical Actionable In a preclinical study, melanoma cell lines with CDKN2A loss demonstrated a greater sensitivity to Alvocidib (flavopiridol) as compared to melanoma cell lines positive for CDKN2A (PMID: 12777976). 12777976