RESUMEN
Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo-like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.
Asunto(s)
Proteína de Unión a CREB/fisiología , Carcinogénesis/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Animales , Proteína de Unión a CREB/genética , Proliferación Celular/genética , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Genómica/métodos , Células HCT116 , Células HEK293 , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Terapia Molecular Dirigida , Mutación , Invasividad Neoplásica , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Lymph node metastases (LNM) in papillary thyroid microcarcinomas (PTMC) are common. PTMC greater than 5 mm are considered to be more aggressive. Tumor greater than 5 mm is predictive factor for occurrence of LNM in PTMC, although there are insufficient data regarding this fact. The purpose of this study was to explore the relation between LNM and patients with small (≤5mm) and large (>5mm) PTMC. The second target was to determine the frequency of multifocality, bilaterality and capsular invasion in small and large PTMC, and their relation with LNM occurrence. METHODS: This study included 257 patients with PTMC. In all patients total thyroidectomy was performed, and lymph node checking of central and lateral neck region using sentinel lymph node (SLN) biopsy in clinically N0 patients, or modified radical neck dissection in clinically N1b patients or in case with positive SLN. RESULTS: LNM were detected in 33% of the patients, 27% in the central neck region and 20% in the lateral neck region with 6.23% of skip metastases. LNM were significantly frequent in large PTMC compared with small (46 vs 24%), in the central region (38 vs 19%) and the lateral region (28 vs 14%), with skip metastases 7.62% and 5.26%, respectively. Bilaterality and capsular invasion were frequent in large PTMC. Multifocality and male gander were predictive factors for LNM in small PTMC, while capsular invasion was the only predictive factor in large PTMC. CONCLUSIONS: Although LNM are frequent in large PTMC, the percentage of LNM is not negligible in small PTMC, especially if they are multifocal.