Novel Targets in Non‐Small Cell Lung Cancer: ROS1 and RET Fusions

The discovery of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in non‐small cell lung cancer (NSCLC) has stimulated renewed interest in oncogenic fusions as potential therapeutic targets. Recently, genetic alterations in ROS1 and RET were identified in patients with NSCLC. Like ALK, genetic alterations in ROS1 and RET involve chromosomal rearrangements that result in the formation of chimeric fusion kinases capable of oncogenic transformation. Notably, ROS1 and RET rearrangements are rarely found with other genetic alterations, such as EGFR, KRAS, or ALK. This finding suggests that both ROS1 and RET are independent oncogenic drivers that may be viable therapeutic targets. In initial screening studies, ROS1 and RET rearrangements were identified at similar frequencies (approximately 1%–2%), using a variety of genotyping techniques. Importantly, patients with either ROS1 or RET rearrangements appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. These features may in turn expedite enrollment in clinical trials evaluating genotype‐directed therapies in these rare patient populations. In this review, we summarize the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in NSCLC. 摘要 参与非小细胞肺癌（NSCLC）间变性淋巴瘤激酶（ALK）基因的染色体重排的发现重新燃起了人们将癌基因融合作为潜在治疗靶点的新兴趣。最近，在NSCLC患者中发现了ROS1和RET 的遗传学改变。与ALK类似，ROS1和RET的遗传学改变涉及染色体重排，并导致具有致癌性转变功能的嵌合融合蛋白激酶形成。尤其是，ROS1和RET重排很少见于其他遗传学改变，如EGFR、KRAS或ALK等。这一发现提示ROS1和RET为独立的致癌驱动子，并可能作为治疗靶点。初期筛查研究发现，在应用不同的基因分型技术情况下，ROS1和RET重排的出现几率均类似（约1% ~ 2%）。重要的是，ROS1和RET重排的患者似乎具有独特的临床和病理学特征，这或许能够推动策略的辨识和改进。这些特征可能反过来加快那些评估基因型特异性治疗用于罕见患者人群的临床试验招募速度。本综述将总结NSCLC中ROS1和RET重排的分子生物学、临床特征、探查及其靶向性。The Oncologist 2013;18:865‐875 This review summarizes the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in non‐small cell lung cancer (NSCLC). Genetic alterations in ROS1 and RET were recently identified in NSCLC patients, and those affected appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. Preclinical data and early clinical data suggest that both ROS1 and RET rearrangements may be viable therapeutic targets.