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Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression
Yoshiki Katsumi1, Tomoko Iehara, Mitsuru Miyachi
1Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-hirokoji, Kyoto 602-8566, Japan.
Abstract:
Malignant rhabdoid tumor (MRT) is a rare and highly aggressive neoplasm of young children. MRT is characterized by inactivation of integrase interactor 1 (INI1). Cyclin-dependent kinase 4 (CDK4), which acts downstream of INI1, is required for the proliferation of MRT cells. Here we investigated the effects of PD 0332991 (PD), a potent inhibitor of CDK4, against five human MRT cell lines (MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS, KP-MRT-YM). In all of the cell lines except KP-MRT-YM, PD inhibited cell proliferation >50%, (IC(50) values 0.01 to 0.6 microM) by WST-8 assay, and induced G1-phase cell cycle arrest, as shown by flow cytometry and BrdU incorporation assay. The sensitivity of the MRT cell lines to PD was inversely correlated with p16 expression (r=0.951). KP-MRT-YM cells overexpress p16 and were resistant to the growth inhibitory effect of PD. Small interfering RNA against p16 significantly increased the sensitivity of KP-MRT-YM cells to PD (p<0.05). These results suggest that p16 expression in MRT could be used to predict its sensitivity to PD. PD may be an attractive agent for patients with MRT whose tumors express low levels of p16.
Insights
PD 0332991 effectively inhibits malignant rhabdoid tumor (MRT) cell proliferation by targeting CDK4. Tumor p16 expression levels predict patient response to this potential MRT therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Malignant rhabdoid tumor (MRT) is a rare, aggressive childhood cancer.
- MRT is associated with integrase interactor 1 (INI1) inactivation.
- Cyclin-dependent kinase 4 (CDK4) drives MRT cell proliferation downstream of INI1.
Purpose of the Study:
- To evaluate the efficacy of PD 0332991 (PD), a CDK4 inhibitor, against human MRT cell lines.
- To determine the correlation between p16 expression and sensitivity to PD in MRT.
- To explore p16 as a predictive biomarker for PD treatment response in MRT.
Main Methods:
- Testing PD 0332991 on five human MRT cell lines.
- Assessing cell proliferation inhibition using WST-8 assay.
- Analyzing cell cycle arrest via flow cytometry and BrdU incorporation.
- Investigating the role of p16 using correlation analysis and small interfering RNA (siRNA).
Main Results:
- PD inhibited proliferation in four of five MRT cell lines (IC50: 0.01–0.6 µM) and induced G1 cell cycle arrest.
- MRT cell sensitivity to PD was inversely correlated with p16 expression (r=0.951).
- p16-overexpressing cells were resistant to PD; p16 siRNA increased sensitivity.
Conclusions:
- PD 0332991 demonstrates significant anti-proliferative effects on most MRT cell lines.
- p16 expression is a key determinant of sensitivity to PD in MRT.
- PD is a promising therapeutic agent for MRT, particularly in tumors with low p16 expression.
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