Nature Milestone: New Target for Non-Small Cell Lung Cancer - CLIP1-LTK

Article source: Medicine Cube Pro

Author: Heart Fruit

According to global statistics, among all types of cancer, lung cancer has the highest mortality rate, accounting for 19% of cancer-related deaths and 3% of total global deaths

The discovery of oncogenic factors sheds light on the pathogenesis of NSCLC

Although the development of corresponding kinase inhibitors has improved treatment strategies and improved patient survival, targeted therapies have not yet been developed for the majority of patients with advanced NSCLC whose tumors lack known oncogenic factors

In a new study published in Nature on November 24, researchers from the National Cancer Center of Japan used the Lung Cancer Genome Screening Platform (LC-SCRUM-Asia) developed by the team to screen potential lung cancer carcinogens through a series of studies.

First, we performed whole-transcriptome sequencing (WTS) of samples from NSCLC cases in which no oncogenes were identified in the LC-SCRUM-Asia screening, and found the CLIP1-LTK oncogene fusion in one of the positive samples

Identification of the CLIP1-LTK fusion (source: Nature)

Next, the researchers demonstrated that the CLIP1-LTK protein can form a dimer (ie, protein dimerization), which activates the CLIP1-LTK kinase

Transformation activity of CLIP1-LTK fusion in vivo (Source: Nature)

Benefiting from the above results, the search for kinase inhibitors of CLIP1-LTK protein will have clinical therapeutic significance

Finally, a patient with CLIP1-LTK-bearing NSCLC who received lorlatinib, the 2- and 5-month follow-up CT images showed rapid and substantial shrinkage of the primary tumor and multiple metastases, and PET images showed all of both primary and metastatic tumors responded to lorlatinib treatment at baseline

Lorlatinib inhibits CLIP1-LTK kinase activity and inhibits tumor growth (Source: Nature)

Collectively, this study is the first to report the relationship between LTK mutations and oncogenic activity, identifying CLIP1-LTK as a novel target in NSCLC that could be treated with lorlatinib in currently untreatable NSCLC patients

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references:

1# Hiroki Izumi, Shingo Matsumoto, Jie Liu, et al.

2# Mohammad-Javad Sanaei, Atieh Pourbagheri-Sigaroodi, Vahid KavehRecent, et al.