Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma

Nakaoku, Takashi; Tsuta, Koji; Ichikawa, Hitoshi; Shiraishi, Kouya; Sanada, Hiromi; Enari, Masato; Furuta, Koh; Shimada, Yôko; Ogiwara, Hideaki; Watanabe, Shun‐ichi; Nokihara, Hiroshi; Yasuda, Kazuki; Hara, Masaki; Nammo, Takao; Ishigame, Teruhide; Schetter, Aaron J.; Okayama, Hirokazu; Harris, Curtis C.; Kim, Young Hak; Mishima, Michiaki; Yokota, Jun; Yoshida, Teruhiko; Kohno, Takashi

doi:10.1158/1078-0432.ccr-14-0107

Cited by 178 publications

(196 citation statements)

References 27 publications

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“…CD74-NRG1 activates ERBB3 as well as PI3K-AKT signaling (34), thus promoting anchorage-independent growth of NIH-3T3 cells (ref. 35; Fig. 1).…”

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

confidence: 94%

“…1). 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).…”

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%

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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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“…CD74-NRG1 activates ERBB3 as well as PI3K-AKT signaling (34), thus promoting anchorage-independent growth of NIH-3T3 cells (ref. 35; Fig. 1).…”

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

confidence: 94%

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

confidence: 99%

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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“…Mucus secreted by cancer cells can commonly be discharged as sputum. However, if airway obstruction happens, obstructive pneumonia occurs immediately, since the mucus fails to drain (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Primary mucinous adenocarcinoma of the lung: A case report and review of the literature

et al. 2017

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Abstract. Mucinous adenocarcinoma is an unusual histological type of lung cancer, and its clinicopathological feature is distinctive from that of other histopathological types of lung adenocarcinoma. Mucinous adenocarcinoma has a mucus-producing function, which explains its name. The present study reports a rare case of a mucus-producing adenocarcinoma of the lung. A 60-year-old Chinese female patient was diagnosed with mucinous adenocarcinoma of the lung, which manifested as respiratory symptoms, including fever, cough and expectoration. The patient received thoracic exploratory operation and right pneumonectomy, since the above respiratory symptoms seriously affected her daily life, and other inspections could not establish the diagnosis. Histopathology revealed no mutations in epidermal growth factor receptor. The patient received adjuvant chemotherapy using taxol and cisplatin. However, metastases in the left lung were detected 7 months after the operation. Pemetrexed and cisplatin were used as the second-line treatment. The patient survived 3 years after the initial diagnosis. The present study reports a rare mucus-producing adenocarcinoma of the lung, which is of bad prognosis. Therefore, further studies on this type of cancer are urgently required. IntroductionLung cancer is the leading cancer in terms of mortality and morbidity in the world, and adenocarcinomas are common histological types of lung cancer (1,2). The International Society for the Study of Lung Cancer (IASLC), the American Thoracic Society and the European Respiratory Society jointly published a histological classification of lung adenocarcinomas in 2011 (3). The main interest of such classification is its prognostic value, since histological type is closely associated with clinical, pathological and molecular parameters (4,5).Mucinous adenocarcinoma is the rarest type of lung adenocarcinoma (6). According to a recent classification (3), mucinous adenocarcinoma includes mucinous adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive mucinous adenocarcinoma. These tumors tend to present KRAS mutations and commonly lack thyroid transcription factor-1 expression, and computed tomography (CT) usually indicates nodules of consolidation with air bronchograms that are generally multinodular and multilobular in distribution (5). Mucinous adenocarcinoma of the lung is morphologically characterized by tall columnar cells with abundant cytoplasm that contain varying amounts of mucin (6,7). Mucus secreted by cancer cells can commonly be discharged as sputum. However, if airway obstruction happens, obstructive pneumonia occurs immediately, since the mucus fails to drain (8-10). Case reportThe patient was a 60-year-old female. On October 2011, the patient developed fever, with a temperature fluctuation between 37.5 and 39.0˚C, in addition to cough and yellow sputum, but no chills or shivering, abdominal pain or diarrhea, sore throat, urinary frequency or urgency, or dysuria. In the Hospital of Traditional Chinese Medicine, a CT scan of t...

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“…Several RET/PTC rearrangements (Table 1) have been described, almost exclusively in PTC cells. The exceptions are a few cases of leukemia and lung adenocarcinomas that show peculiar and exclusive RET/ PTC rearrangements that have not yet been reported in PTC (Ballerini et al 2012, Kohno et al 2012, Lira et al 2014, Nakaoku et al 2014. The prevalence of RET/PTCpositive cases is approximately 20%, and it has apparently been decreasing in recent decades (Romei et al 2012).…”

Section: Molecular Alterations In Thyroid Cancer and The Rationale Fomentioning

confidence: 99%

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Viola

Valerio

Molinaro

et al. 2016

Endocrine-Related Cancer

167

130

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Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

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Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma

Cited by 178 publications

References 27 publications

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer

Primary mucinous adenocarcinoma of the lung: A case report and review of the literature

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

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