RESUMEN
Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. ONE SENTENCE SUMMARY: Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.
Asunto(s)
Quinasa de Linfoma Anaplásico , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Compuestos Organofosforados , Inhibidores de Proteínas Quinasas , Proteoma , Familia-src Quinasas , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Humanos , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismo , Ratones , Proteoma/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Pirimidinas/farmacología , Proteómica/métodos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.
Asunto(s)
Crizotinib , Neoplasias Pulmonares , Nanopartículas Magnéticas de Óxido de Hierro , Microambiente Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Microambiente Tumoral/efectos de los fármacos , Animales , Nanopartículas Magnéticas de Óxido de Hierro/química , Humanos , Ratones , Crizotinib/farmacología , Crizotinib/química , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Línea Celular Tumoral , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Proliferación Celular/efectos de los fármacos , FemeninoRESUMEN
Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2+ breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κß) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1+ macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κß signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κß inhibitors with current treatments.
Asunto(s)
Neoplasias de la Mama , Inestabilidad Cromosómica , Tolerancia Inmunológica , Quinasa Tipo Polo 1 , Escape del Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Humanos , Animales , Ratones , Quinasa Tipo Polo 1/genética , Quinasa Tipo Polo 1/metabolismo , Línea Celular Tumoral , Receptor ErbB-2/genética , FN-kappa B/metabolismo , Antígeno B7-H1/metabolismo , Receptor de Manosa/metabolismo , Células Asesinas Naturales/inmunología , Xenoinjertos , Células MCF-7 , FemeninoRESUMEN
BACKGROUND: RNA editing has been described as promoting genetic heterogeneity, leading to the development of multiple disorders, including cancer. The cytosine deaminase APOBEC3B is implicated in tumor evolution through DNA mutation, but whether it also functions as an RNA editing enzyme has not been studied. RESULTS: Here, we engineer a novel doxycycline-inducible mouse model of human APOBEC3B-overexpression to understand the impact of this enzyme in tissue homeostasis and address a potential role in C-to-U RNA editing. Elevated and sustained levels of APOBEC3B lead to rapid alteration of cellular fitness, major organ dysfunction, and ultimately lethality in mice. Importantly, RNA-sequencing of mouse tissues expressing high levels of APOBEC3B identifies frequent UCC-to-UUC RNA editing events that are not evident in the corresponding genomic DNA. CONCLUSIONS: This work identifies, for the first time, a new deaminase-dependent function for APOBEC3B in RNA editing and presents a preclinical tool to help understand the emerging role of APOBEC3B as a driver of carcinogenesis.
Asunto(s)
Neoplasias , Edición de ARN , Humanos , Animales , Ratones , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Mutación , Neoplasias/patología , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , ADN/metabolismoRESUMEN
Se realizó un estudio prospectivo, comparativo, utilizando en azar en un grupo de pacientes y controles con el objetivo de evaluar el resultado clínico de la administración de Glutamina por vía oral a niños menores de 5 años con diarrea aguda, a dosis de 0,5 gr/Kg/ una vez al día; para el análisis de los resultados se utilizó estadística descriptiva, y la t Student como prueba de significancia estadística. Se encontró que el promedio de edad al ingreso fue en el grupo estudio de 8,3 meses y en el grupo control de 7,7 meses. La diarrea aguda representó el 64 por ciento de los casos y la disentería aguda el 35 por ciento, y en el frupo control tanto la diarrea aguda como la disentería aguda representaron 50 por ciento. En el grupo estudio control la mayoría ingresó con algún grado de deshidratación, 52 y 62 por ciento respectivamente. Se comparó el peso de ingreso y peso de egreso en ambos grupos, encontrándose en el grupo estudio aumento de peso, siendo estadísticamente significativo (p<0,05). La asociación de cuadros patológicos concomitantes y trastornos bioquímicos en ambos grupos, complicaron la evolución clínica. La estancia hospitalaria en el grupo estudio fue de 8 días (t observando = 0,3 y t crítico = 1,31) y de 7,1 días en el grupo control (t observando = 0,42 y t crítico = 0,68) resultados estadísticamente no significativos. En este grupo de investigación la glutamina favoreció el aumento de peso, quedando abiertas las expectativas a nuevas experiencias en manejo terapéutico de la diarrea