RESUMEN
The development of multiple vascular endothelial growth factor- and mammalian target of rapamycin-targeted therapies in advanced renal cell carcinoma has resulted in significant clinical benefit. However, the availability of multiple treatment options has led to a more complicated clinical decision-making process. Prognostic factors have been incorporated into the inclusion criteria for pivotal clinical trials and have thus provided some guidance regarding the selection and sequencing of therapy. Even within a given patient risk group and particular line of therapy, questions remain regarding the optimal choice of a targeted agent. The present review provides a practical, clinician-oriented assessment of pharmacologic factors that should be considered when a receptor tyrosine kinase or mammalian target of rapamycin kinase inhibitor is used to treat patients with advanced or metastatic renal cell carcinoma. Although these 2 classes of agents have different mechanisms of action, they are metabolized by similar pathways, resulting in broadly similar pharmacokinetic and drug-drug interaction profiles. To further individualize therapy and optimize clinical benefit, an enhanced understanding of the key pharmacologic features that differentiate these agents is important.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Carcinoma de Células Renales/metabolismo , Toma de Decisiones Clínicas , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Humanos , Neoplasias Renales/metabolismo , Medicina de Precisión , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage-fusion-bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR-CHEK1 pathway, and that knocking down the ATR-CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR-CHEK1 pathway and flow cytometry showed G2 M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR-CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF-00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR-CHEK1 pathway inhibition.
Asunto(s)
Carcinoma de Células Escamosas/genética , Cromosomas Humanos Par 11/genética , Neoplasias de la Boca/genética , Proteínas Quinasas/genética , Tolerancia a Radiación , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Carcinoma de Células Escamosas/radioterapia , Línea Celular Tumoral/efectos de la radiación , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Deleción Cromosómica , Segregación Cromosómica , Daño del ADN , Técnicas de Silenciamiento del Gen , Humanos , Puntos de Control de la Fase M del Ciclo Celular , Neoplasias de la Boca/radioterapia , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Transducción de Señal , Regulación hacia ArribaRESUMEN
The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.