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RET fusion

V Subbiah, V Velcheti, B B Tuch, K Ebata, N L Busaidy, M E Cabanillas, L J Wirth, S Stock, S Smith, V Lauriault, S Corsi-Travali, D Henry, M Burkard, R Hamor, K Bouhana, S Winski, R D Wallace, D Hartley, S Rhodes, M Reddy, B J Brandhuber, S Andrews, S M Rothenberg, A Drilon
Purpose: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and Methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models...
April 18, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Xuan Liu, Tao Shen, Blaine H M Mooers, Frank Hilberg, Jie Wu
BACKGROUND AND PURPOSE: RET alterations are found in thyroid and lung cancer. While RET tyrosine kinase inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer (NSCLC), the impact of mutations in the RET kinase domain on drug sensitivity was largely uncharacterized. EXPERIMENTAL APPROACH: We identified and analyzed mutations in the RET kinase domain that conferred resistance to the TKIs cabozantinib, lenvatinib, vandetanib, and nintedanib using RET kinase-dependent BaF3/KIF5B-RET (BaF3/KR) cells...
June 16, 2018: British Journal of Pharmacology
Zunfu Ke, Yihao Liu, Yunjian Zhang, Jie Li, Ming Kuang, Sui Peng, Jinyu Liang, Shuang Yu, Lei Su, Lili Chen, Cong Sun, Bin Li, Jessica Cao, Weiming Lv, Haipeng Xiao
Differentiation of benign and malignant thyroid nodules is crucial for clinical management. Here, we explored the efficacy of next‑generation sequencing (NGS) in predicting the classification of benign and malignant thyroid nodules and lymph node metastasis status, and simultaneously compared the results with ultrasound (US). Thyroline was designed to detect 15 target gene mutations and 2 fusions in 98 formalin‑fixed, paraffin‑embedded (FFPE) tissues, including those from 82 thyroid cancer (TC) patients and 16 patients with benign nodules...
June 14, 2018: Oncology Reports
Masafumi Saiki, Satoru Kitazono, Takahiro Yoshizawa, Yosuke Dotsu, Ryo Ariyasu, Junji Koyama, Tomoaki Sonoda, Ken Uchibori, Shingo Nishikawa, Noriko Yanagitani, Atsushi Horiike, Fumiyoshi Ohyanagi, Katsunori Oikado, Hironori Ninomiya, Kengo Takeuchi, Yuichi Ishikawa, Makoto Nishio
BACKGROUND: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented. PATIENTS AND METHODS: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics...
May 10, 2018: Clinical Lung Cancer
Alexa B Schrock, Viola W Zhu, Wen-Son Hsieh, Russell Madison, Benjamin Creelan, Jeffrey Silberberg, Dan Costin, Anjali Bharne, Ioana Bonta, Thangavijayan Bosemani, Petros Nikolinakos, Jeffrey S Ross, Vincent A Miller, Siraj M Ali, Samuel J Klempner, Sai-Hong Ignatius Ou
INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR TKIs. METHODS: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (FFPE tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians...
June 5, 2018: Journal of Thoracic Oncology
E Dahl
BACKGROUND: Over the last 15 years, an estimated 3000 large centralized biobanks have been established worldwide, making important contributions to the further development of precision medicine. In many cases, these biobanks are affiliated with pathological institutes or work closely with them. OBJECTIVE: In which translational research projects, and during which phases in the development of new drugs are human bioprobes being used and can their use be easily traced in the literature? METHODS: PubMed, Internet research, and information from the German Biobank Alliance and the European initiative BBMRI-ERIC...
June 6, 2018: Der Pathologe
(no author information available yet)
LOXO-292, a selective and potent RET inhibitor, led to tumor shrinkage in RET fusion-positive and RET -mutant cancers alike, according to phase I data reported at the 2018 American Society of Clinical Oncology Annual Meeting.
May 31, 2018: Cancer Discovery
Cheng Wang, Rong Yin, Juncheng Dai, Yayun Gu, Shaohua Cui, Hongxia Ma, Zhihong Zhang, Jiaqi Huang, Na Qin, Tao Jiang, Liguo Geng, Meng Zhu, Zhening Pu, Fangzhi Du, Yuzhuo Wang, Jianshui Yang, Liang Chen, Qianghu Wang, Yue Jiang, Lili Dong, Yihong Yao, Guangfu Jin, Zhibin Hu, Liyan Jiang, Lin Xu, Hongbing Shen
Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0...
May 24, 2018: Nature Communications
Timothy VandenBoom, Victor L Quan, Bin Zhang, Erin M Garfield, Betty Y Kong, Maria C Isales, Elnaz Panah, Catherine Igartua, Timothy Taxter, Nike Beaubier, Kevin White, Pedram Gerami
Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions...
May 22, 2018: American Journal of Surgical Pathology
Liming Cao, Long Long, Min Li, Huaping Yang, Pengbo Deng, Xinru Mao, Jianxing Xiang, Bing Li, Tengfei Zhang, Chengping Hu
Purpose: The development of next-generation sequencing (NGS) has revolutionized the understanding of oncogenesis of multiple types of cancer, including non-small cell lung cancer (NSCLC). However, there has been some debate over the utility of NGS for predicting patient prognosis and determining molecular targeted therapy. Therefore, we sought to demonstrate the numerous applications of NGS in the prognostic predictions and treatment of NSCLC patients. Materials and methods: We performed NGS on either liquid or tissue tumor biopsies obtained from 53 NSCLC patients...
2018: OncoTargets and Therapy
Huiling He, Wei Li, Pearlly Yan, Ralf Bundschuh, Jackson A Killian, Jadwiga Labanowska, Pamela Brock, Rulong Shen, Nyla A Heerema, Albert de la Chapelle
BACKGROUND: The BRAFV600E mutation is the most common driver in papillary thyroid carcinoma (PTC) tumors. In recent years, gene fusions have also been recognized as important drivers of cancer in PTC. Previous studies have suggested that thyroid tumors with fusion genes frequently display an aggressive course. These observations prompted further exploration of gene fusions in PTC tumors. The aim was to search for previously unrecognized gene fusions using thyroid tissue samples from PTC patients...
May 16, 2018: Thyroid: Official Journal of the American Thyroid Association
Simon Andreasen, Katalin Kiss, Linea C Melchior, Jan Laco
No abstract text is available yet for this article.
July 2018: American Journal of Surgical Pathology
Hestia S Mellert, Kristin E Alexander, Leisa P Jackson, Gary A Pestano
We have developed novel methods for the isolation and characterization of tumor-derived circulating ribonucleic acid (cRNA) for blood-based liquid biopsy. Robust detection of cRNA recovered from blood represents a solution to a critical unmet need in clinical diagnostics. The test begins with the collection of whole blood into blood collection tubes containing preservatives that stabilize cRNA. Cell-free, exosomal, and platelet-associated RNA is isolated from plasma in this test system. The cRNA is reverse transcribed to complementary DNA (cDNA) and amplified using digital polymerase chain reaction (dPCR)...
April 5, 2018: Journal of Visualized Experiments: JoVE
Wenxin Luo, Panwen Tian, Yue Wang, Heng Xu, Lu Chen, Chao Tang, Yang Shu, Shouyue Zhang, Zhoufeng Wang, Jun Zhang, Li Zhang, Lili Jiang, Lunxu Liu, Guowei Che, Chenglin Guo, Hong Zhang, Jiali Wang, Weimin Li
Non-small-cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never-smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never-smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger...
April 18, 2018: International Journal of Cancer. Journal International du Cancer
Vivek Subbiah, Justin F Gainor, Rami Rahal, Jason D Brubaker, Joseph L Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P Sheets, Douglas Wilson, Kevin J Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I Hu, Lori Wirth, Marcia S Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi, Erica K Evans
The receptor tyrosine kinase, rearranged during transfection (RET), is an oncogenic driver activated in multiple cancers including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC). No approved therapies have been designed to target RET; treatment has been limited to multi-kinase inhibitors (MKIs) which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations...
April 15, 2018: Cancer Discovery
C Santos, R Sanz-Pamplona, R Salazar
No abstract text is available yet for this article.
April 10, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Qingsong Gao, Wen-Wei Liang, Steven M Foltz, Gnanavel Mutharasu, Reyka G Jayasinghe, Song Cao, Wen-Wei Liao, Sheila M Reynolds, Matthew A Wyczalkowski, Lijun Yao, Lihua Yu, Sam Q Sun, Ken Chen, Alexander J Lazar, Ryan C Fields, Michael C Wendl, Brian A Van Tine, Ravi Vij, Feng Chen, Matti Nykter, Ilya Shmulevich, Li Ding
Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types...
April 3, 2018: Cell Reports
Rebecca Ronsley, S Rod Rassekh, Yaoqing Shen, Anna F Lee, Colleen Jantzen, Jessica Halparin, Catherine Albert, Douglas S Hawkins, Shazhan Amed, Ralph Rothstein, Andrew J Mungall, David Dix, Geoffrey Blair, Helen Nadel, Steven J M Jones, Janessa Laskin, Marco A Marra, Rebecca J Deyell
Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding...
April 2018: Cold Spring Harbor Molecular Case Studies
Nadezda P Velizheva, Markus P Rechsteiner, Nadejda Valtcheva, Sandra N Freiberger, Christine E Wong, Bart Vrugt, Qing Zhong, Ulrich Wagner, Holger Moch, Sven Hillinger, Isabelle Schmitt-Opitz, Alex Soltermann, Peter J Wild, Verena Tischler
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases)...
April 2018: Pathology, Research and Practice
Xuefei Zhang, Yanlin Li, Changhong Liu, Weifeng Wang, Mo Li, Desheng Lv, Ge Sun, Hui Chen, Xiaowei Dong, Zhibo Miao, Ming Yao, Kai Wang, Hui Tian
RET fusions have been reported in 1-2% of lung adenocarcinomas, and represent an actionable target. Patients whose tumors possess RET fusion are associated with clinical benefit from the treatment with multi-kinase inhibitors such as cabozantinib and vandetanib. Further molecular screening for RET fusions is warranted. Novel KIF13A-RET fusion containing an intact RET kinase domain involving exons 1-18 of KIF13A and exons 12-20 of RET was identified in a lung cancer specimen from an 74-year-old Asian never smoker by next-generation sequencing (NGS) during clinical care...
April 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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