RESUMEN
Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug resistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients.
Asunto(s)
Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MicroARNs/genética , Células Madre Neoplásicas/patología , Quinasas p21 Activadas/genética , Animales , Regulación Leucémica de la Expresión Génica/genética , Xenoinjertos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones SCID , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/fisiología , Quinasas p21 Activadas/metabolismoRESUMEN
Background: Glioblastoma (GBM) is associated with fatal outcomes and devastating neurological presentations especially impacting the elderly. Management remains controversial and representation in clinical trials poor. We generated 2 nomograms and a clinical decision making web tool using real-world data. Methods: Patients ≥60 years of age with histologically confirmed GBM (ICD-O-3 histology codes 9440/3, 9441/3, and 9442/3) diagnosed 2005-2015 were identified from the BC Cancer Registry (n = 822). Seven hundred and twenty-nine patients for which performance status was captured were included in the analysis. Age, performance and resection status, administration of radiation therapy (RT), and chemotherapy were reviewed. Nomograms predicting 6- and 12-month overall survival (OS) probability were developed using Cox proportional hazards regression internally validated by c-index. A web tool powered by JavaScript was developed to calculate the survival probability. Results: Median OS was 6.6 months (95% confidence interval [CI] 6-7.2 months). Management involved concurrent chemoradiation (34%), RT alone (42%), and chemo alone (2.3%). Twenty-one percent of patients did not receive treatment beyond surgical intervention. Age, performance status, extent of resection, chemotherapy, and RT administration were all significant independent predictors of OS. Patients <80 years old who received RT had a significant survival advantage, regardless of extent of resection (hazard ratio range from 0.22 to 0.60, CI 0.15-0.95). A nomogram was constructed from all 729 patients (Harrell's Concordance Index = 0.78 [CI 0.71-0.84]) with a second nomogram based on subgroup analysis of the 452 patients who underwent RT (Harrell's Concordance Index = 0.81 [CI 0.70-0.90]). An online calculator based on both nomograms was generated for clinical use. Conclusions: Two nomograms and accompanying web tool incorporating commonly captured clinical features were generated based on real-world data to optimize decision making in the clinic.