<i>CD74–NRG1</i> Fusions in Lung Adenocarcinoma

Fernández-Cuesta, Lynnette; Plenker, Dennis; Osada, Hirofumi; Sun, Ruping; Menon, Roopika; Leenders, Frauke; Ortiz-Cuarán, Sandra; Peifer, Martin; Bos, Marc; Daßler, Juliane; Malchers, Florian; Schöttle, Jakob; Vogel, Wenzel; Dahmen, Ilona; Koker, Mirjam; Ullrich, Roland T.; Wright, Gavin; Russell, Prudence A.; Wainer, Zoe; Solomon, Benjamin; Brambilla, Élisabeth; Nagy-Mignotte, Hélène; Moro-Sibilot, Denis; Brambilla, Christian; Lantuéjoul, Sylvie; Altmüller, Janine; Becker, Christian; Nürnberg, Peter; Heuckmann, Johannes M.; Stoelben, Erich; Petersen, Iver; Clement, Joachim H.; Sänger, Jörg; Muscarella, Lucia Anna; Torre, Annamaria la; Fazio, Vito Michele; Lahortiga, Idoya; Perera, Timothy; Ogata, Souichi; Paradé, Marc; Brehmer, Dirk; Vingron, Martin; Heukamp, Lukas C.; Buettner, Reinhard; Zander, Thomas; Wolf, Jürgen; Perner, Sven; Ansén, Sascha; Haas, Stefan A.; Yatabe, Yasushi; Thomas, Roman K.

doi:10.1158/2159-8290.cd-13-0633

Cited by 240 publications

(261 citation statements)

References 21 publications

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“…Furthermore, NRG1 fusion-mediated signaling could be suppressed by clinically approved kinase inhibitors (35). NRG1 fusions are preferentially found in women who had never smoked, and whose tumors are negative for other known mutant oncogenic gene mutations such as those in KRAS [frequently mutated in invasive mucinous adenocarcinoma (IMA)], or EGFR (34,35). In another study, CD74-NRG1-positive tumors displayed uncommon radiologic features in comparison with what it is usually seen in IMA (36).…”

Section: Erbb1 (Egfr; Ref 1) Erbb2 (Her2; Ref 2) Erbb3mentioning

confidence: 98%

“…Finally, analyses of prostate cancer cells and tumors suggest the existence of a paracrine loop involving NRG1 and the ERBB2-ERBB3 heterodimer (33). We recently discovered recurrent CD74-NRG1 gene fusions, which result in the expression of the NRG1 III-b3 isoform in the otherwise NRG1-negative invasive mucinous subtype of lung adenocarcinomas (34). CD74-NRG1 activates ERBB3 as well as PI3K-AKT signaling (34), thus promoting anchorage-independent growth of NIH-3T3 cells (ref.…”

Section: Erbb1 (Egfr; Ref 1) Erbb2 (Her2; Ref 2) Erbb3mentioning

confidence: 99%

“…NRG1 fusions are the first potentially treatable oncogenic driver alteration associated with a specific lung adenocarcinoma subtype and in contrary to KRAS mutations, which are associated with tobacco use, NRG1 fusions occur in KRAS-negative IMA of never smokers. Taking all together, the discovery of recurrent, oncogenic, and possibly targetable NRG1 fusions may represent a therapeutic opportunity for these tumors (34,35).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…Because NRG1 fusions act through activation of ERBB2-ERBB3 heterodimers (34), blocking the activity of these receptors may be the best strategy to treat NRG1-rearranged tumors. Similar to EGFR and ERBB4, the extracellular domain of ERBB3 probably exists in two different conformations: a tethered autoinhibited form and an untethered ligand-bound form (41).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

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Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Fernández-Cuesta

Thomas

2015

Clinical Cancer Research

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The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand-receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1, which represent a novel mechanism for ERBB pathway deregulation. These fusions lead to expression and presentation of the EGF-like domain of NRG1 on the cell surface, which binds to ERBB3 in an autocrine and juxtacrine manner, thus inducing the formation of ERBB2-ERBB3 heterodimers, and subsequent activation of the PI3K-AKT and MAPK signaling pathways. These fusion genes were exclusively detected in lung adenocarcinomas of never smokers of the invasive mucinous subtype, which usually presents as a multifocal and unresectable disease, for which no effective treatment exists. Considering the large amount of drugs that target ERBB2 (HER2) and ERBB3 (HER3), and which are currently in different stages of clinical development, detecting and targeting NRG1 fusions in invasive mucinous lung adenocarcinomas may represent a therapeutic opportunity for this aggressive disease. Clin Cancer Res; 21(9); 1989-94. Ó2014 AACR.

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Section: Erbb1 (Egfr; Ref 1) Erbb2 (Her2; Ref 2) Erbb3mentioning

confidence: 98%

Section: Erbb1 (Egfr; Ref 1) Erbb2 (Her2; Ref 2) Erbb3mentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Fernández-Cuesta

Thomas

2015

Clinical Cancer Research

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“…With pathological findings proving more valuable than nonaddictive molecular biomarkers (KRAS, MSH2 and TUBB3) for choosing the optimal treatment, our data confirmed that chemotherapy should be preferred over EGFR-TKIs for patients with mucinous L-ADC. However, several novel somatic gene fusions could represent a therapeutic opportunity for advanced mucinous L-ADC, a tumour for which no effective treatment exists, except chemotherapy, and which frequently presents with multifocal unresectable disease [43,44].…”

Section: Discussionmentioning

confidence: 99%

Erlotinibversuscarboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504

Cadranel¹,

Gervais²,

Merle³

et al. 2015

Eur Respir J

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The IFCT-0504 phase II trial evaluated the efficacy of erlotinib versus carboplatin-paclitaxel (CP) as first-line treatment in 130 cases of advanced lepidic-predominant adenocarcinoma (ADC).The primary objective of the study was treatment efficacy, evaluated based on an end-point of disease control at 16 weeks.The primary objective was met, with a disease control in 35 (53%) out of 66 patients treated with CP and in 25 (39.1%) out of 64 patients treated with erlotinib. Median progression-free survival (PFS) for the total population was 3.6 months. The disease control rate did not differ between either the therapeutic arms or pathological subtypes, whereas there was a strong interaction between treatment arms and tumour pathological subtypes for PFS ( p=0.009). Mucinous tumour patients treated with erlotinib exhibited an increased progression risk (hazard ratio 3.4, 95% CI 1.7-6.5; p⩽0.001). The PFS for nonmucinous tumour patients was similar in both arms. Median overall survival was 20.1 months and did not differ between therapeutic arms. These findings were not further elucidated by molecular analyses and the toxicity profiles were as expected.Our study demonstrated the dominant role of CP alongside erlotinib in the management of advanced lepidic ADC. Based on these findings, erlotinib should not be administered in first-line therapy to patients with lepidic ADC in the absence of an epidermal growth factor receptor mutation. @ERSpublications Interaction between pathological subtypes and treatment (erlotinib/chemotherapy) in advanced lepidic adenocarcinoma

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NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma

et al. 2016

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Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28–87% of the cases. NRG1 fusions were recently discovered in KRAS‐negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed. In the IMA samples remaining negative for these driver oncogenes, an NRG1 rearrangement detection was performed by FISH. A driver oncogene was identified in 14/25 IMA, namely 12 KRAS mutations (48%), one ROS1 rearrangement (4%), and one ALK rearrangement (4%). The detection of NRG1 rearrangement by FISH was conducted in the 11 pan‐negative IMA. One sample was NRG1 FISH‐positive and 100% of the tumor nuclei analyzed were positive. This NRG1‐positive patient was a 61‐year‐old nonsmoking woman of Vietnamese ethnicity and was the sole patient of Asian ethnicity of the cohort. She died 6 months after the diagnosis with a pulmonary multifocal disease. NRG1 FISH detection should be considered in patients with IMA pan‐negative for known driver oncogenes. These results might suggest that NRG1 fusion is more frequent in IMA from Asian patient. Larger studies are needed.

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CD74–NRG1 Fusions in Lung Adenocarcinoma

Cited by 240 publications

References 21 publications

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Erlotinibversuscarboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504

NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma

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