RESUMEN
Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.
Asunto(s)
Proteínas de Ciclo Celular , Neoplasias Pulmonares , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-myc , Humanos , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Línea Celular Tumoral , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ratones , Animales , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína LigasasRESUMEN
BACKGROUND: Despite the implementation of patient-centred care, mental health issues remain a significant risk factor and comorbidity for Tuberculosis (TB) disease. Mental health issues being co-morbidities to TB are likely to increase the disease burden of the affected population. This study therefore investigated the prevalence and impact of mental health issues in Tuberculosis (TB) patients. METHODS: This cross-sectional study design used mixed methods in data collection. The study used structured questionnaires, key informant interviews and focus group discussions. 127 TB patients were purposively selected from a group of patients who previously recovered successfully, with a history of relapse or are currently on TB treatment in high-volume facilities in Homa Bay, Busia and Kakamega Counties. 30 Key informant interviews were conducted with Healthcare workers. Quantitative data analysis was done using STATA version 14. Thematic analysis was employed to analyze qualitative data using NVivo version 10. RESULTS: The findings showed that the most common mental health issues affecting TB patients were anxiety (66%) and depression (55%), which were commonly experienced during the presumptive stage of TB. Qualitative data revealed that stigma was the main barrier that hindered TB patients from accessing care. TB patients articulated the benefits of support structures ranging from positive encouragement, reminders on taking drugs, accompaniment to the clinic, and financial support in TB management. Furthermore, the study established that the majority of Health Care Workers (HCWs) were not prepared to handle TB patients' mental issues, a gap that is likely to impact the quality of care TB patients receive. CONCLUSION: The study established that mental health issues impact TB treatment outcomes. Healthcare systems should prioritize the integration of mental health care into TB programs to address the high prevalence of mental health issues among TB patients.
