TTC7A-ALK, a novel ALK fusion variant identified in a patient with metastatic lung adenocarcinoma, exhibits excellent response to crizotinib

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. ALK gene rearrangement has been identified in 3 % to 5 % of the patients with NSCLC. Thanks to the advancements in second-generation sequencing technology, an increasing number of novel fusion partners have been identified. In our research, we discovered a rare ALK fusion, TTC7A-ALK, in a patient with advanced lung adenocarcinoma using targeted next-generation sequencing (NGS). After being diagnosed with advanced lung adenocarcinoma with TTC7A-ALK fusion, the patient received crizotinib treatment and achieved a progression-free survival of 29 months. Additonanlly, we conducted further functional analyses on this fusion protein to assess its oncogenic potential. Similar to EML4-ALK, the TTC7A-ALK fusion protein can promote the growth of Ba/F3 cells under IL-3-independent conditions in vitro. In vivo studies demonstrate that the TTC7A-ALK fusion protein could enhance the tumorigenesis of NIH3T3 cells in nude mice, which can be suppressed by crizotinib. Mechanistic studies indicated that the ectopic expression of TTC7A-ALK in 293T cells led to the hyperactivation of downstream MAPK and PI3K/Akt pathways, which can be inhibited by crizotinib. Furthermore, upon tumor progression, the patient transitioned to alectinib, which provided rapid symptom relief and controlled the majority of lesions. Conclusionly, we identified and validated TTC7A-ALK as a oncogenic fusion in NSCLC. The patient demonstrated a significant clinical benefit from sequential treatment with crizotinib and alectinib, highlighting TTC7A-ALK as a novel therapeutic target for ALK inhibitors. These findings extend the spectrum of actionable ALK fusions and promote the inclusion of rare fusion detection in clinical diagnostic processes and treatment strategies.