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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer
Ka-Won Noh1,2, Mi-Sook Lee1,2, Seung Eun Lee3
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Korea.
Abstract:
Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) (p = 0.057, p < 0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners (GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take the ALK molecular profiling into consideration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insights
Molecular profiling of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) variants, novel ALK mutations, and fusion partners in non-small cell lung cancer impacts ALK inhibitor sensitivity. Understanding these factors is crucial for effective targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) often responds to ALK inhibitors, but primary resistance mechanisms remain unclear.
- Previous research on ALK fusions in NSCLC has been limited by small cohorts or in vitro/in vivo studies.
- The role of echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants in differential sensitivity to ALK inhibitors is a proposed theory.
Purpose of the Study:
- To conduct a large-scale, comprehensive molecular analysis of ALK-rearranged NSCLCs.
- To investigate the impact of EML4-ALK variants, novel ALK mutations, and fusion partners on ALK inhibitor response.
- To correlate molecular findings with clinical outcomes in NSCLC patients.
Main Methods:
- Extensive molecular analysis of 158 ALK-rearranged NSCLC cases.
- Cell line construct experiments to validate in vitro findings.
- Targeted deep sequencing to identify novel ALK fusion partners and mutations.
Main Results:
- NSCLCs with EML4-ALK short forms exhibited more advanced stages and frequent metastases compared to long forms.
- In vitro experiments demonstrated lower sensitivity to ALK inhibitors for EML4-ALK short forms.
- Four novel somatic ALK mutations (T1151R, R1192P, A1280V, L1535Q) conferring primary resistance were identified, along with three novel ALK fusion partners (GCC2, LMO7, PHACTR1).
Conclusions:
- EML4-ALK variants, novel somatic ALK mutations, and new ALK-fusion partners significantly influence sensitivity to ALK inhibitors in NSCLC.
- Molecular profiling of ALK in NSCLC is essential for guiding targeted therapy decisions.
- These findings underscore the importance of personalized medicine approaches in treating ALK-rearranged NSCLC.
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