Phase separation of EML4–ALK in firing downstream signaling and promoting lung tumorigenesis

Using two genetically engineered mouse models (GEMMs), we find that EML4–ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4–ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4–ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4–ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4–ALK fusion. READ ARTICLE

Cell Discovery DOI: 10.1038/s41421-021-00270-5

Authors: Zhen Qin, Honghua Sun, Meiting Yue, Xinwen Pan, Liang Chen, Xinhua Feng, Xiumin Yan, Xueliang Zhu, Hongbin Ji

Pre-ClinicalKirk SmithMay 5, 2021EML4-ALK fusion, variant 1, STAT3

A case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer

Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient’s right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/com..... READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1212

Authors: Xu X, Liu D, Wen J, Chen J, Fan M.

Case StudyKirk SmithDecember 9, 2020Lung cancer, EML4-ALK, variant 1