Reference Detail

Ref Type Journal Article
PMID (22862161)
Authors Slovackova J, Smarda J, Smardova J
Title Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53.
Journal Neoplasma
Vol 59
Issue 6
Date 2012
URL
Abstract Text Roscovitine, an inhibitor of cyclin-dependent kinases, is promising anticancer agent. Its antiproliferative and cytotoxic effects can be mediated by the p53 signaling pathway. To define the role of p53 in roscovitine-induced cell response, we prepared H1299/p53 cell lines inducibly expressing specific variants of p53 (p53wt and hotspot R175H, temperature-dependent P98A, A159V, S215G, Y220C, Y234C mutants). In the presence of roscovitine, each cell line variant behaved in specific way reflecting activity of the p53 protein. Roscovitine decreased production of the cell cycle inhibitor p21 and induced apoptosis. This effect was the most efficient in cells expressing p53wt protein with full activity. The cell expressing partially and conditionally active p53 mutants responded to roscovitine less efficiently. The cells expressing p53 mutants A159V and Y234C were very sensitive to roscovitine but their response was clearly temperature-dependent. The cells expressing P98A, S215G and Y220C p53 mutants exhibited only weak sensitivity to roscovitine and underwent apoptosis in low frequency. In principle, each td p53 mutant responded to roscovitine in distinct way. We showed clearly that the impact of roscovitine on H1299 cells depends on functional status of p53 they produce. This suggests that patients with tumors exhibiting specific p53 variants can benefit from the roscovitine therapy.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
A159V missense loss of function TP53 A159V lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). A159V results decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild type Tp53 in cell culture (PMID: 22862161).
P98A missense loss of function TP53 P98A lies within the WWOX-interacting region of the Tp53 protein (UniProt.org). P98A results in decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild-type Tp53 in cell culture (PMID: 22862161, PMID: 20505364).
S215G missense loss of function TP53 S215G lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). S215G results in decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild type Tp53 in cell culture (PMID: 22862161).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 R175H lung non-small cell carcinoma resistant Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 R175H were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 Y220C lung non-small cell carcinoma resistant Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 Y220C were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 P98A lung non-small cell carcinoma decreased response Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 P98A demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 S215G lung non-small cell carcinoma resistant Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 S215G were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 negative lung non-small cell carcinoma decreased response Seliciclib Preclinical - Cell culture Actionable In a preclinical study, TP53-null non-small cell lung carcinoma cells demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 A159V lung non-small cell carcinoma decreased response Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 A159V demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 Y234C lung non-small cell carcinoma decreased response Seliciclib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 Y234C demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161). 22862161
TP53 wild-type lung non-small cell carcinoma sensitive Seliciclib Preclinical - Cell culture Actionable In a preclinical study, Roscovotine (seliciclib) induced substantial apoptosis in non-small cell lung carcinoma cells overexpressing wild-type TP53 in culture (PMID: 22862161). 22862161