Minari Roberta, Valentini Samuel, Madeddu Denise, Cavazzoni Andrea, La Monica Silvia, Lagrasta Costanza Anna Maria, Bertorelli Roberto, De Sanctis Veronica, Fassan Paola, Azzoni Cinzia, Bottarelli Lorena, Frati Caterina, Gnetti Letizia, Facchinetti Francesco, Petronini Pier Giorgio, Alfieri Roberta, Romanel Alessandro, Tiseo Marcello
Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
JTO Clin Res Rep. 2022 Jan 20;3(2):100278. doi: 10.1016/j.jtocrr.2022.100278. eCollection 2022 Feb.
ALK tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced ALK-positive NSCLC. Nevertheless, drug resistance inevitably occurs. Here, we report a case of a patient with metastatic ALK-positive lung adenocarcinoma with an impressive resistance to sequential treatment with ALK TKIs mediated by and amplification in a contest of epithelial-to-mesenchymal transition and high progressive chromosomal instability.
The patient received, after chemotherapy and 7 months of crizotinib, brigatinib and lorlatinib with no clinical benefit to both treatments. A study of resistance mechanisms was performed with whole exome sequencing on different biological samples; primary cell lines were established from pleural effusion after lorlatinib progression.
At whole exome sequencing analysis, and amplifications were observed both in the pericardial biopsy and the pleural effusion samples collected at brigatinib and lorlatinib progression, respectively. Increasing chromosomal instability from diagnostic biopsy to pleural effusion was also observed. The addition of dasatinib to brigatinib or lorlatinib restored the sensitivity in primary cell lines; data were confirmed also in H3122_ALK-positive model overexpressing both and .
In conclusion, and amplifications are candidates to justify a rapid acquired resistance to crizotinib entailing primary brigatinib and lorlatinib resistance. In this context, a combination strategy of ALK TKI with dasatinib could be effective to overcome a rapid resistance.
间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKIs）是晚期ALK阳性非小细胞肺癌（NSCLC）的标准治疗方法。然而，耐药性不可避免地会出现。在此，我们报告一例转移性ALK阳性肺腺癌患者，在经历上皮-间质转化和高进展性染色体不稳定的情况下，因 和 扩增介导，对ALK TKIs序贯治疗产生显著耐药。
该患者在接受化疗和7个月的克唑替尼治疗后，使用布加替尼和劳拉替尼均未获得临床益处。通过对不同生物样本进行全外显子测序来研究耐药机制；在劳拉替尼进展后从胸腔积液中建立原代细胞系。
在全外显子测序分析中，分别在布加替尼和劳拉替尼进展时采集的心包活检样本和胸腔积液样本中观察到 和 扩增。从诊断性活检到胸腔积液还观察到染色体不稳定性增加。在原代细胞系中，将达沙替尼添加到布加替尼或劳拉替尼中可恢复敏感性；在同时过表达 和 的H3122_ALK阳性模型中也证实了该数据。
总之， 和 扩增可能是导致对克唑替尼快速获得性耐药并引发对布加替尼和劳拉替尼原发性耐药的原因。在这种情况下，ALK TKI与达沙替尼的联合策略可能有效克服快速耐药。
