NUMERO: #20250416

Título: WHOLE-EXOME SEQUENCING REVEALS RESISTANCE PATHWAYS IN PDX ADENOID CYSTIC CARCINOMA TREATED WITH ENTINOSTAT AND CISPLATIN

Nome do Apresentador: Luccas LAVAREZE

Categoria do Trabalho: Painel de pesquisa científica (PPC)

Área Temática: Estomatologia

Resumo: Objective: To investigate the genomic and functional impact of Entinostat, a HDAC1 inhibitor, and cisplatin on adenoid cystic carcinoma (ACC) patient-derived xenograft (PDX) model using whole-exome sequencing (WES). Study Design: ACCX6 tumor was implanted in immunodeficient mice (N=12) and treated with vehicle, Entinostat (5 mg/kg), cisplatin (3 mg/kg), or their combination. Neither Entinostat nor cisplatin alone affected tumor response, while combination showed a modest effect. WES was performed on tumor DNA, with variant identification followed by functional enrichment analyzed through Gene Ontology and Reactome pathways, considering only protein-impacting variants with p<0.05 significance using false discovery rate method. Results: All treatments increased variant counts. RUNX3-mediated cell cycle arrest (CDKN1A transcription) was enriched by all treatments (p<0.001). Entinostat enriched extracellular matrix (ECM) organization pathways, while cisplatin showed collagen-related and ECM degradation pathways. Combination therapy significantly promoted ECM-related pathways (p<0.001), with enrichment of MMP, ADAM, and COL genes, glucuronidation, downregulation of Wnt signaling (p<0.001), chromatin and histone methylation-related genes. Analysis of oncogenes and tumor suppressor genes revealed p53 pathway activation (p=0.0002) in cisplatin-related treatments and HDAC1 persistence in the combination group. Conclusion: ACCX6 exhibited significant genomic alterations upon treatment, suggesting potential resistance mechanisms through RUNX3-mediated cell cycle arrest and ECM remodeling.

Autor 1:  Luccas LAVAREZE

E-mail 1:  [email protected]

Autor 2:   Sheila Tiemi NAGAMATSU

E-mail 2:  [email protected]

Autor 3 :  Luciana Souto MOFATTO

E-mail 3:  [email protected]

Autor 4:  Álfio José TINCANI

E-mail 4:  [email protected]

Autor 5:  Carlos Takahiro CHONE

E-mail 5:  [email protected]

Autor 6:  Rogério Moraes de CASTILHO

E-mail 6:  [email protected]

Autor 7:  Fernanda Viviane MARIANO

E-mail 7:  [email protected]