Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Thoracic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210032, China.
Lung Cancer. 2022 Sep;171:18-25. doi: 10.1016/j.lungcan.2022.07.011. Epub 2022 Jul 19.
Crizotinib remains one of the most commonly used targeted therapies for ALK fusion-positive patients. However, the mutational profiles and mechanisms of resistance to first-line crizotinib treatment remain to be thoroughly examined.
We retrospectively reviewed 125 ALK-positive patients with histological and/or cytological diagnosis of NSCLC. Of these, baseline samples were available from 62 patients and 63 had resistance samples following first-line crizotinib treatment, with 18 patients having paired baseline and resistance samples. All patients were genetically profiled by NGS using a 139 lung cancer gene panel (Pulmocan®, Nanjing Geneseeq Technology Inc.). Survival associations of progression-free survival (PFS) and resistance mechanisms were evaluated in relation to ALK fusion variants and background genetic alterations.
The median age of the cohort was 53 years old (range 26-78; 46.4 % females). Three novel ALK fusion partners were identified, including PSME4, cullin3 (CUL3) and coiled-coil domain containing 85A (CCDC85A). Among the different ALK fusion genes, patients carrying the v3 variant experienced worse PFS outcome compared with other non-v3 fusions (P = 0.01) in response to first-line crizotinib. Profiling of the genetic landscape revealed TP53 as the most frequently co-mutated gene, alterations of which were associated with unfavorable outcome (P = 0.024) and were among the secondary acquired mutations in the resistance samples. Examinations of the resistance mechanisms showed that the v3 variant was more likely to acquire ALK activating mutations (P = 0.04). Off-target resistance mechanisms included mutations in genes in the RAS/MAPK and its parallel pathway genes, such as ERBB2, BRAF, KRAS, FGFR3, NF1 and CREBBP.
In this study, through profiling of the mutational landscape of ALK-positive advanced NSCLCs both at baseline and disease progression, we characterized resistance mechanisms and molecular correlations of PFS in response to first-line crizotinib. Our findings may facilitate rational selection of subsequent ALK TKIs in the clinic.
克唑替尼仍然是治疗 ALK 融合阳性患者最常用的靶向治疗药物之一。然而，一线克唑替尼治疗耐药的突变特征和机制仍需深入研究。
我们回顾性分析了 125 例组织学和/或细胞学诊断为 NSCLC 的 ALK 阳性患者。其中，62 例患者有基线样本，63 例患者在一线克唑替尼治疗后有耐药样本，18 例患者有基线和耐药配对样本。所有患者均采用 139 个肺癌基因panel（南京世和基因生物技术有限公司）通过 NGS 进行基因谱分析。评估无进展生存期（PFS）和耐药机制与 ALK 融合变异和背景遗传改变的相关性。
该队列的中位年龄为 53 岁（范围 26-78；46.4%为女性）。共鉴定出三种新的 ALK 融合伙伴，包括 PSME4、cullin3（CUL3）和 coiled-coil domain containing 85A（CCDC85A）。在不同的 ALK 融合基因中，携带 v3 变异的患者在一线克唑替尼治疗中 PFS 结果更差，与其他非-v3 融合相比（P=0.01）。遗传景观分析显示 TP53 是最常共突变的基因，其改变与不良预后相关（P=0.024），并在耐药样本中属于继发性获得性突变。耐药机制的研究表明，v3 变异更可能获得 ALK 激活突变（P=0.04）。非靶向耐药机制包括 RAS/MAPK 及其平行途径基因（如 ERBB2、BRAF、KRAS、FGFR3、NF1 和 CREBBP）中的基因突变。
本研究通过对 ALK 阳性晚期 NSCLC 患者的基线和疾病进展时的突变景观进行分析，明确了一线克唑替尼治疗耐药的机制和 PFS 的分子相关性。我们的发现可能有助于在临床中合理选择后续的 ALK TKI。
