ABSTRACT
PURPOSE: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. EXPERIMENTAL DESIGN: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46). RESULTS: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05). CONCLUSIONS: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Piperazines/therapeutic use , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Breast Neoplasms/blood , Breast Neoplasms/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/blood , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/blood , Drug Resistance, Neoplasm , Female , Humans , Middle Aged , Neoplasm Metastasis , Protein Kinase Inhibitors/therapeutic use , Receptors, Estrogen/metabolism , Survival Rate , Thymidine Kinase/blood , Treatment SwitchingABSTRACT
BACKGROUND: Cyclin dependent kinases (CDK) are key factors in promoting the initiation and development of tumors. These kinases are important for maintenance of mitochondrial biogenesis and imbalance in their expression in old age may lead to the oxidative stress. Lung cancer (LC), and head and neck squamous cell carcinoma (HNSCC) are two very prominent cancers in older Indians. Both the cancers are showing increasing trend in older population. The present study assessed serum concentration of one of the kinases; CDK4 in older LC and HNSCC patients. METHODS: The study included 100 subjects each of LC and HNSCC; and older subjects without cancer or any major health problems as controls. Serum CDK4 concentration was estimated using real-time label-free Surface plasmon resonance (SPR) and was verified by western blot. RESULTS: Significant elevation in serum CDK4 was observed in cases with LC and HNSCC compared to controls. HNSCC patients with higher CDK4 expression had distinctly shorter survival than patients with comparatively lower CDK4 expression. No such difference was observed in LC patients. The germ line mutation study of this gene in Exon-2 was performed and none was observed among cases and controls. CONCLUSION: It can be concluded that older patients with HNSCC and lung cancer have raised serums CDK4 levels, which has the potential to emerge as a biomarker in clinical practice.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Squamous Cell/blood , Cyclin-Dependent Kinase 4/blood , Head and Neck Neoplasms/blood , Lung Neoplasms/blood , Aged , Blotting, Western , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Polymerase Chain Reaction , Squamous Cell Carcinoma of Head and Neck , Surface Plasmon ResonanceABSTRACT
OBJECTIVE: Despite refinement of surgical techniques and adjuvant radiotherapy, the prognosis for patients with a chordoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment and result in molecular markers for targeted therapy. Limited studies have been performed to unravel the impact of cell-cycle markers in chordoma, and those performed have shown inconclusive results. In the current study, we aimed to discover the impact of cyclin-dependent kinase 4 (CDK4) expression and its relation to prognosis and other cell-cycle markers in chordoma. METHODS: Twenty-five human formalin-fixed, paraffin-embedded chordoma specimens were examined by immunohistochemistry for the expression of CDK4, protein 53 (p53), and murine double minute 2 (MDM2). The MIB-1 labeling index and mitotic index were used for the examination of proliferation. We collected detailed demographic and clinical data. RESULTS: Overexpression of CDK4, p53, and MDM2 was found in five (20%), seven (28%), and 14 (56%) of the cases, respectively. All three cell-cycle markers showed a significant correlation with MIB1 labeling index. Expression of CDK4 (P = 0.02) and p53 (P < 0.01) were both significantly correlated with poor overall survival. Also, histologically observed necrosis (P < 0.05) and a dedifferentiated tumor subtype (P < 0.01) were related to adverse patient outcome. CONCLUSION: Our results show that the expression of CDK4 and p53 are related to cell proliferation capacity and worse outcome in patients with chordoma.
