Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

胰腺腺泡细胞癌 (PACC) 是一种罕见的胰腺癌，通常存在可靶向的改变，包括 MAPK 通路中的激活融合和 DNA 损伤反应/同源重组 DNA 修复相关基因的功能丧失 (LOF) 改变。在这里，我们描述了一名患有 PACC 的患者，该患者同时具有NBN的体细胞双等位基因 LOF和激活的NTRK1融合。使用亚叶酸、氟尿嘧啶、伊立替康和奥沙利铂 (FOLFIRINOX) 治疗 13 个月后疾病进展，转移性肝活检的基因组分析显示出现了一种新的回复突变，恢复了NBN的阅读框架。据我们所知，NBN的基因组逆转此前尚未被报道为任何肿瘤类型的耐药机制。该患者接受了选择性 NTRK 抑制剂的靶向治疗，但没有反应。该案例凸显了 PACC 复杂但高度可操作的基因组景观，并强调了 PACC 等罕见肿瘤类型基因组分析的价值。