肺腺癌中一种新型 MYO5C-ALK 融合:alectinib 反应有限而 lorlatinib 获益持久
A novel MYO5C-ALK fusion in lung adenocarcinoma: limited alectinib response and durable lorlatinib benefit.
作者
作者单位
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
- Department of Pathology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
- Department of Radiology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. Electronic address: arron12182012@gmail.com.
摘要
中文
间变性淋巴瘤激酶 (ALK) 重排驱动约 5% 的非小细胞肺癌 (NSCLC),最常见的形式为 EML4-ALK,但罕见的 5' 端融合伙伴可能赋予不同的药理学行为。本文报告首例携带新型 MYO5C (exon 23)-ALK (exon 20) 融合的肺腺癌。诊断和耐药分析采用基于 DNA 和 RNA 的二代测序 (NGS)、免疫组织化学 (IHC) 及系列影像学检查,并利用 AutoDock Vina 对患者来源的融合激酶与 alectinib 和 lorlatinib 进行计算机分子对接模拟。一例 72 岁从不吸烟的 IVB 期肺腺癌患者携带框内 MYO5C-ALK 融合,保留了完整的 ALK 酪氨酸激酶域。患者接受一线 alectinib 治疗后约 7 个月肿瘤进展,尽管再次活检未发现获得性 ALK 激酶域突变、TP53 突变或旁路改变(突变阴性耐药),随后改用 lorlatinib 获得持久部分缓解(无进展生存期 >15 个月)。我们推测 MYO5C-ALK 嵌合体可能因融合伙伴驱动的组成性二聚化持续激活激酶信号,而 alectinib 抑制不完全;lorlatinib 具有更高的 potency 和大环刚性,可能恢复对结构完整激酶的持久抑制。计算机对接结果与该假说一致,显示 ATP 结合口袋保留,且 lorlatinib 的结合模式锚定更为广泛,与已知的 potency 差异相吻合。首例 MYO5C-ALK 融合的报道提出了假设性的生物学机制——即伙伴驱动的二聚化被更强效的大环抑制剂克服——以解释 ALK 抑制剂反应的差异,并支持 lorlatinib 用于非典型融合及突变阴性的二代 TKI 耐药患者。
English
Anaplastic lymphoma kinase (ALK) rearrangements drive approximately 5% of non-small cell lung cancers (NSCLC), most commonly as EML4-ALK, but rare 5' partners may confer distinct pharmacologic behaviour. We report the first lung adenocarcinoma harbouring a novel MYO5C (exon 23)-ALK (exon 20) fusion. Diagnosis and resistance profiling used DNA- and RNA-based next-generation sequencing (NGS), immunohistochemistry (IHC) and serial imaging. In silico molecular docking of alectinib and lorlatinib against the patient-derived fusion kinase was performed with AutoDock Vina. A 72-year-old never-smoker with stage IVB lung adenocarcinoma harboured an in-frame MYO5C-ALK fusion retaining the entire ALK tyrosine kinase domain. The tumour progressed at approximately seven months on first-line alectinib despite re-biopsy showing no acquired ALK kinase-domain mutation, no TP53 mutation or bypass alteration (mutation-negative resistance), then achieved a durable partial response to lorlatinib (progression-free survival > 15 months). We hypothesise that constitutive, partner-driven dimerisation of the MYO5C-ALK chimera may sustain kinase signalling that alectinib incompletely suppresses, whereas the higher potency and macrocyclic rigidity of lorlatinib could restore durable inhibition of the structurally intact kinase. In silico docking is consistent with this hypothesis, showing a preserved ATP-binding pocket and a more extensively anchored binding mode for lorlatinib concordant with the known potency differential. This first report of a MYO5C-ALK fusion proposes a hypothesised biological rationale - partner-driven dimerisation overcome by a more potent macrocyclic inhibitor - for the differential ALK-inhibitor response, and supports lorlatinib for atypical fusions and for mutation-negative second-generation tyrosine kinase inhibitor (TKI) resistance.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 5.3
- 新锐分区
- 2区