Les réarrangements moléculaires : cibles thérapeutiques en cancérologie thoracique Fusion transcripts: Therapeutic targets in thoracic oncology

Five to ten percent of lung adenocarcinoma harbor chromosomal rearrangements affecting the ALK, ROS1, NTRK and RET genes. These rearrangements are associated with the production of fusion transcripts that lead to the synthesis of chimeric proteins with constitutive kinase activity. These abnormal proteins induce an oncogenic dependency that may be targeted by tyrosine kinase inhibitors. In this review, we will summarize the clinical and molecular epidemiology of chromosomal rearrangements affecting ALK, ROS1, NTRK and RET genes. We will describe the mechanisms of resistance to tyrosine kinase inhibitors that have been reported. We will present the molecular techniques that can be used to detect these rearrangements and the strategies set-up by the molecular oncology laboratories to diagnose these genetic alterations. READ ARTICLE

Bulletin du Cancer DOI:10.1016/j.bulcan.2020.05.008

Authors: Audrey Mansuet-Lupo, Simon Garinet, Diane Damotte, Marco Alifano, Hélène Blons, Marie Wislez, Karen Leroy

Review PaperKirk SmithSeptember 1, 2020Rearrangement, Fusion, ALK, ROS1, RET, NTRK

A novel SOS1-ALK fusion variant in a patient with metastatic lung adenocarcinoma and a remarkable response to crizotinib

Objectives: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. Conclusion: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.02.012

Authors: Hua-fei Chen, Wen-xian Wang, Chun-wei Xu, Li-chao Huang, Xiao-feng Li, Gang Lan, Zhan-qiang Zhai, You-cai Zhu, Kai-qi Du, Lei Lei, Mei-yu Fang

Case StudyKirk SmithApril 1, 2020Non-Small cell lung cancer, ALK, Fusion, TKI, Crizotinib

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements

Introduction: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs. Conclusions: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI-induced ALK oncogenic activation in IMTs. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.003

Authors: Jason C. Chang, Lei Zhang, Alexander E. Drilon, Ping Chi, Rita Alaggio, Laetitia Borsu, Ryma Benayed, William D. Travis, Marc Ladanyi, Cristina R. Antonescu