Molecular and clinicopathological characteristics of <i>ROS1</i>‐rearranged non‐small‐cell lung cancers identified by next‐generation sequencing

Cui, Meiying; Han, Yuchen; Pan, Li; Zhang, Jianying; Ou, Qiuxiang; Tong, Xiaoling; Zhao, Ruiying; Dong, Nan; Wu, Xue; Li, Wencai; Jiang, Guozhong

doi:10.1002/1878-0261.12789

Cited by 38 publications

(36 citation statements)

References 32 publications

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“…The fusion product retained the entire ROS1 tyrosine kinase domain. SDC4 is a common fusion partner of ROS1 , constituting for 13% of ROS1 fusion in Chinese patients, and intron 2 for SDC4 and intron 31 for ROS1 are common breakpoint point locations ( 14 ). Patients with SDC4-ROS1 rearrangement were enrolled into the clinical study to access the efficacy of crizotinib in NSCLC patients with ROS1 fusion.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

Chen

Hong

et al. 2021

Front. Med.

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ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

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Section: Discussionmentioning

confidence: 99%

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

Chen

Hong

et al. 2021

Front. Med.

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“…The results of several studies showed that the presence of CD74-ROS-1 rearrangement was associated with longer progression-free survival (PFS) and overall survival (OS) than non-CD74-ROS-1 rearrangement [36]. However, that association with survival was not found in other studies [34].…”

Section: Fusion Partnersmentioning

confidence: 98%

Section: Molecular Characteristicsmentioning

confidence: 99%

“…ROS-1 rearrangement occurs at a breakpoint in the ROS gene at the 5′ end of exons 32, 34, 35, or 36, or introns 31 or 33 [ 14 , 34 ]. The most frequently seen fusion partners ( Table 1 ) are CD74 (38–54%), EZR (13%–24%), SDC4 (9–13%), and SLC34A2 (5–10%) [ 34 , 35 ]. However, improved DNA- and RNA-sequencing techniques have enabled identification of numerous fusion partners, including CCCKC6 , TFG, SLMAP, MYO5C, FIG, LIMA1, CLTC, GOPC, ZZCCHC8, CEP72, MLL3, KDELR2, LRIG3, MSN, MPRIP, WNK1, SLC6A17, TMEM106B, FAM135B, TPM3, and TDP52L1 [ 36 ].…”

Section: Molecular Characteristicsmentioning

confidence: 99%

“…In vitro, concomitant administration of SHP2 and TKI inhibitors better inhibited tumor growth and constitutes a promising avenue of research [ 125 ]. Activation of other signaling pathways, such as KIT, PI3K, and EGFR, has also been reported [ 34 ]. In the second case, mutations of ALK [ 125 ], BRAF [ 126 ], KRAS, neuroblastoma rat-sarcoma viral oncogene (NRAS) [ 34 ], and MET [ 127 ] genes and MET amplifications [ 128 ] have been described.…”

Section: Ros-1-positive Nsclc Resistance Mechanismsmentioning

confidence: 99%

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ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

et al. 2022

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The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.

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Current treatment and novel insights regarding ROS1‐targeted therapy in malignant tumors

Li,

Zhang,

Chen

et al. 2024

Cancer Medicine

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BackgroundThe proto‐oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self‐mutations or rearrangements. Studies on ROS1‐directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next‐generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage.MethodIn this study, we searched relevant articles reporting the mechanism and clinical application of ROS1 in recent years; systematically reviewed the biological mechanisms, diagnostic methods, and research progress on ROS1 inhibitors; and provided perspectives for the future of ROS1‐targeted therapy.ResultsROS1 is most expressed in malignant tumours. Only a few ROS1 kinase inhibitors are currently approved for use in NSCLC, the efficacy of other TKIs for NSCLC and other malignancies has not been ascertained. There is no effective standard treatment for adverse events or resistance to ROS1‐targeted therapy. Next‐generation TKIs appear capable of overcoming resistance and delaying central nervous system metastasis, but with a greater incidence of adverse effects.ConclusionsFurther research on next‐generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.

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Molecular and clinicopathological characteristics of ROS1‐rearranged non‐small‐cell lung cancers identified by next‐generation sequencing

Cited by 38 publications

References 32 publications

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

Current treatment and novel insights regarding ROS1‐targeted therapy in malignant tumors

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