ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy

Onco Pub Date : 2023-08-22 DOI:10.3390/onco3030014
U. Testa, G. Castelli, E. Pelosi
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Abstract

Non-small-cell lung cancer (NSCLC) is a heterogeneous group of diseases accounting for 80–85% of lung cancers. A molecular subset of NSCLC (1–2.5%) harboring molecular rearrangements of the tyrosine kinase gene ROS1 is defined as ROS1-positive and is almost exclusively diagnosed in patients with lung adenocarcinoma histology, predominantly nonsmokers. ROS1 is constitutively activated by molecular rearrangements and acts as a main driver of lung carcinogenesis. These findings have provided a strong rationale for the clinical use of tyrosine kinase inhibitors that target ROS1; these inhibitors block ROS1-positive NSCLC and provide clinical benefit. Crizotinib was introduced as a first-line treatment for ROS1-positive NSCLCs, with 75–80% of patients responding and a PFS of about 20 months. More recently developed ROS1-TKIs, such as entrectinib, lorlatinib, taletrectinib, repotrectinib and NVL-520, are active against some resistant ROS1 mutants appearing during crizotinib therapy and more active against brain metastases, frequent in ROS1-positive NSCLC. The development of resistance mechanisms represents a great limitation for the targeted treatment of ROS1-positive NSCLCs with TKIs.
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ROS1重排肺腺癌:从分子遗传学到靶向治疗
非小细胞肺癌(NSCLC)是一种异质性疾病,占肺癌的80-85%。酪氨酸激酶基因ROS1分子重排的NSCLC分子亚群(1-2.5%)被定义为ROS1阳性,几乎只在肺腺癌组织学患者中诊断,主要是非吸烟者。ROS1被分子重排激活,是肺癌发生的主要驱动因素。这些发现为临床使用靶向ROS1的酪氨酸激酶抑制剂提供了强有力的理论依据;这些抑制剂阻断ros1阳性的NSCLC并提供临床益处。克唑替尼作为ros1阳性nsclc的一线治疗,75-80%的患者有反应,PFS约为20个月。最近开发的ROS1- tkis,如enterrectinib、lorlatinib、taletrectinib、repotrectinib和nbl -520,对克里唑替尼治疗期间出现的一些耐药ROS1突变体有活性,对脑转移更有活性,常见于ROS1阳性的NSCLC。耐药机制的发展对TKIs靶向治疗ros1阳性nsclc具有很大的局限性。
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