Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Nat Commun. 2023 May 5;14(1):2601. doi: 10.1038/s41467-023-38195-0.
Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.
间变性淋巴瘤激酶（ALK）的激活点突变使 ALK 成为神经母细胞瘤中唯一可针对靶向治疗的突变致癌基因。这些突变的细胞在临床前研究中对 lorlatinib 有反应，为 ALK 驱动的神经母细胞瘤患儿的首次 1 期临床试验（NCT03107988）提供了依据。为了跟踪肿瘤的进化动态和异质性，并检测 lorlatinib 耐药的早期出现，我们从参加该试验的患者中收集了一系列循环肿瘤 DNA 样本。在这里，我们报告了在 11 名患者（27%）中发现的非靶点耐药突变，主要在 RAS-MAPK 通路中。我们还在 6 名（15%）患者中发现了新获得的继发性复合 ALK 突变，均在疾病进展时获得。功能细胞和生化分析以及计算研究阐明了 lorlatinib 耐药机制。我们的研究结果确立了连续循环肿瘤 DNA 采样在跟踪反应和进展以及发现获得性耐药机制方面的临床应用价值，这些机制可用于开发克服 lorlatinib 耐药性的治疗策略。
