Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion

... We discuss the initial report of a myelin transcription factor 1 like gene (MYT1L)-ALK fusion identified in the tumor of a patient with metastatic NSCLC, and the tumor's unique response to treatment... In this case, NGS revealed a large duplication event in chromosome 2, resulting in a novel MYT1L-ALK fusion. Myelin transcription factor 1-like protein is located on the cytoplasmic surface of the Golgi membranes and the endoplasmic reticulum and is an important factor in the cell cycle (specifically, in checkpoint recovery).4 Because ALK fusion partners may be a determinant of response to treatment and its possible future resistance type,5 detection of these fusions is crucial. Fluorescence in situ hybridization testing for ALK failed to detect the fusion in either the primary lung cancer and the liver metastases. The ability of NGS to detect ALK fusions and their fusion partners may increase patients’ therapeutic options. Identifying novel events such as the MYT1L-ALK fusion may b..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.169

Authors: Terrence C. Tsou, Kyle Gowen, Siraj M. Ali, Vincent A.Miller, Alexa B. Schrock, Christine M. Lovly, Karen L. Reckamp

EditorialKirk SmithFebruary 1, 2019ALK Inhibitors, NSCLC, MYT1L-ALK Fusion

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all “single mutant active” with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of “single mutant active” ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) “double mutant active” ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2021.101191

Authors: Sai-Hong Ignatius Ou, Misako Nagasaka, Danielle Brazel, Yujie Hou, Viola W.Zhu

Squamous Transition of Lung Adenocarcinoma and Drug Resistance

Studies in mouse models support an essential role of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transition (AST) in the development of drug resistance. Recent observations in the clinic further suggest that this type of histological transition may be responsible for resistance to tyrosine kinase inhibitor (TKI) therapy and chemotherapy in relapsed EGFR-mutant lung ADC patients. Here we summarize the current understanding of AST and drug resistance. READ ARTICLE

Trends in Cancer DOI:10.1016/j.trecan.2016.08.002

Authors: Shenda Hou, Xiangkun Han, Hongbin Ji

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

... We report a case of LCNEC harboring a novel PLB1-ALK rearrangement sensitive to crizotinib by next-generation sequencing (NGS). The patient’s disease responded to crizotinib for > 5 months... NGS demonstrates an additional advantage of being able to concurrently detect different mutations in genetic testing and plays an important role in detecting ALK-rearranged non–small-cell lung cancer. Screening for ALK rearrangement by NGS in patients with LCNEC may help in selecting potential candidates for targeted therapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.026

Authors: Shuai Wang, Xuan Wu, Jiuzhou Zhao, Haiyang Chen, Zhe Zhang, Mingyue Wang, Cong Xu, Yongsen Wang, Lili Wang, Zhen He, Qiming Wang