A group of Chinese researchers have extensively studied kinase fusions in lung cancer, in the hope of providing valuable evidence for therapeutic decision making.
Unfortunately, patients with lung cancer have a 5-year survival rate of around 20%. Non-small cell lung cancer specifically accounts for around 85% of all lung cancers. The main subtypes include adenocarcinoma (ADC), squamous cell carcinoma (SCC), adeno-squamous cell carcinoma (ASC) and large cell carcinoma (LCC). Although they are often grouped together due to their similar treatment and prognosis, the underlying molecular features of these subtypes are unique. Therefore, the identification of oncogenic driver genes is highly important to encourage the advent of more personalised therapies for lung cancer.
What are kinase fusions?
Kinase fusions are a major type of somatic mutation that promote oncogenesis and act as a diagnostic marker in lung cancer. They are produced by translocations or other chromosomal structural rearrangements and their protein products can often function as potential targets for the development of cancer drugs.
Advances in next-generation sequencing (NGS) technologies have enabled the characterisation of kinase fusions among different lung cancer subtypes. However, only 6% of cancer patients currently benefit from the existing drugs that target these fusions. Therefore, the identification of novel druggable kinase fusions is crucial for expanding the therapeutic options for cancer patients and improving the outcome for people suffering from lung cancer.
Studying kinase fusions
Recently, a team of researchers conducted a study, published in npj Precision Oncology, that aimed to explore clinically relevant and rare kinase fusions in lung cancer. The team used DNA sequencing data from over 17,400 Chinese lung cancer patients to identify potential driver fusions. They also analysed the clinical and pathological characteristics of patients with different kinase fusions to explore distinguished molecular differences between non-small lung cancer subtypes.
The scientists were able to perform genomic profiling of 425 cancer-relevant genes. Below are some of the key findings:
- Nearly 7% of patients contained kinase fusions, with the most common kinases being ALK, RET, ROS1, EGFR, and FGFR3.
- In ADC, 170 unique fusion pairs were observed, including rare kinase fusions such as SLC12A2-ROS1, NCOA4-RET, and ANK3-RET.
- In SCC, 15 unique kinase fusions were identified, with the most frequent being EML4-ALK and FGFR3-TACC3.
- The dual role of gene fusions CCDC6-RET and FGFR3-TACC3 was important in driving oncogenesis or acting as acquired resistance mechanisms to kinase inhibitors.
- Most patients with CCDC6-RET and FGFR3-TACC3 fusions were male, whereas VCL-ALK and SDC4-ROS1 fusions were more frequent in females.
Revealing novel druggable fusions
The scientists also integrated mutation, copy number variation and fusion data to evaluate the genomic alterations related to drug administration. For example, patients with stage 5 ADC who had RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favourable clinical outcomes on tyrosine kinase inhibitors. This suggests that information about the relationships between fusions and mutations may lead to the development of effective treatment strategies.
Collectively, these results show that driver mutations can often co-occur and play critical roles in kinase fusions during lung cancer progression. Moreover, it provides a comprehensive overview of the clinical outcomes and molecular features of lung cancer patients, in turn assisting in the recognition of potentially druggable fusions. It is hoped that this knowledge will translate into new or improved therapeutic options for a disease that is notoriously difficult to treat.
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