Dramatic Response to Crizotinib in a Patient With Lung Cancer Positive for an <i>HLA-DRB1-MET</i> Gene Fusion

Davies, Kelvin J.A.; Ng, Terry L.; Estrada-Bernal, Adriana; Le, Anh‐Tuan; Ennever, Peter R.; Camidge, D. Ross; Aisner, Dara L.

doi:10.1200/po.17.00117

Cited by 59 publications

(61 citation statements)

References 22 publications

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“…Clinically, the TRP-MET rearrangement has been discovered in gastric carcinoma [20] , [27] , but not in lung cancer. In NSCLC, we demonstrated the existence of the KIF5B-MET (K24;M15) fusion, together with recently reported HLA-DRB1-MET gene fusion [28] , were similar to TRP-MET in that it also lacks the c-Cbl binding site and might be one of the possible mechanism which drives its oncogenic function. Aside from this, other possible mechanism, such as auto-dimerization, could also drive tumor growth.…”

Section: Discussionsupporting

confidence: 66%

Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

Gow

Liu

et al. 2018

Neoplasia

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A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1–24 of KIF5B and exons 15–21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients.

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Section: Discussionsupporting

confidence: 66%

Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

Gow

Liu

et al. 2018

Neoplasia

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“…Results from circulating tumor DNA were permissible if molecular test results from tissue were not available. The methodology for molecular tests used in this study, including next‐generation sequencing, fluorescent in situ hybridization, amplification refractory mutation system analysis, IHC, and Archer RNA FusionPlex, was according to standard protocols …”

Section: Methodsmentioning

confidence: 99%

Predictive value of oncogenic driver subtype, programmed death‐1 ligand (PD‐L1) score, and smoking status on the efficacy of PD‐1/PD‐L1 inhibitors in patients with oncogene‐driven non–small cell lung cancer

Ng¹,

Liu

Dimou³

et al. 2018

Cancer

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BACKGROUND: This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. METHODS: The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. RESULTS: In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. CONCLUSIONS: Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.

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“…The assay was performed as previously described. 11 Total nucleic acid was used as the input material. Libraries were sequenced via the Illumina MiSeq or NextSeq instruments and raw sequence data was processed with the ArcherDx Analysis software package (version 4.1.1.7, ArcherDx).…”

Section: Rna-based Ngsmentioning

confidence: 99%

DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer

Davies

Lomboy

Lawrence

et al. 2019

Journal of Thoracic Oncology

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118

125

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Introduction: Genomic variants that lead to MET proto-oncogenem receptor tyrosine kinase (MET) exon 14 skipping represent a potential targetable molecular abnormality in NSCLC. Consequently, reliable molecular diagnostic approaches that detect these variants are vital for patient care.Methods: We screened tumor samples from patients with NSCLC for MET exon 14 skipping by using two distinct approaches: a DNA-based next-generation sequencing assay that uses an amplicon-mediated target enrichment and an RNA-based next-generation sequencing assay that uses anchored multiplex polymerase chain reaction for target enrichment.Results: The DNA-based approach detected MET exon 14 skipping variants in 11 of 856 NSCLC samples (1.3%). The RNA-based approach detected MET exon 14 skipping in 17 of 404 samples (4.2%), which was a statistically significant increase compared with the DNA-based assay. Among 286 samples tested by both assays, RNA-based testing detected 10 positives, six of which were not detected by the DNA-based assay. Examination of primer binding sites in the DNA-based assay in comparison with published MET exon 14 skipping variants revealed genomic deletion involving primer binding sequences as the likely cause of false negatives. Two samples positive via the DNA-based approach were uninformative via the RNA-based approach due to poor-quality RNA.Conclusions: By circumventing an inherent limitation of DNA-based amplicon-mediated testing, RNA-based analysis detected a higher proportion of MET exon 14 skipping cases. However, RNA-based analysis was highly reliant on RNA quality, which can be suboptimal in some clinical samples.

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Dramatic Response to Crizotinib in a Patient With Lung Cancer Positive for an HLA-DRB1-MET Gene Fusion

Cited by 59 publications

References 22 publications

Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

Predictive value of oncogenic driver subtype, programmed death‐1 ligand (PD‐L1) score, and smoking status on the efficacy of PD‐1/PD‐L1 inhibitors in patients with oncogene‐driven non–small cell lung cancer

DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer

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