A new study has developed the largest and most comprehensive molecular map to date of lung squamous cell carcinoma (LSCC). Analysis of the data collected has revealed potential therapeutic targets, which are urgently needed to help fight against this type of cancer.
Lung squamous cell carcinoma
LSCC is a leading cause of cancer death worldwide, with only a few treatment options available. Targeted therapies have benefited patients with lung adenocarcinomas (LUAD), but they have not been successful for LSCC patients. This is driven by a lack of knowledge of potential genomic targets in LSCC. Therefore, an increased understanding of this disease is required to develop new treatments.
In this study, proteomic, transcriptomic and genomic data was brought together to characterise the proteogenomic landscape of LSCC. This provides an incredibly detailed description of LSCC biology and has allowed the researchers to develop a much deeper understanding of this cancer.
Therapeutic targets for lung squamous cell carcinoma
The researchers performed deep-scale molecular analysis on 108 primary LSCC tumours and compared this with analysis of 99 paired normal adjacent tissues (NATs). Analysis of this data allowed for identification of potential new drug targets as well as cellular signalling pathways between multiple post-translational modifications (PTMs). PTMs are key to protein activity and signalling, which are processes often targeted in drug discovery.
Many LSCC tumours include increased numbers of the gene FGFR1, which is involved in key processes such as cell division and formation of blood vessels. Previous studies have attempted to target FGFR1, but all so far have failed. Proteomics data collected in this study suggests that the gene NSD3 is in fact the driver of tumorigenesis in FGFR1-amplifed tumours, nominating it as an attractive therapeutic target.
Another gene overexpressed in LSCC tumours is SOX2, which is currently considered undruggable. However, analysis of the team’s data suggests a potential way around this problem. The chromatin modifier LSD1 is a regulator of SOX2 expression and was identified as a vulnerable drug target. Excitingly, the effect of its inhibition on the disease progression of LSCC is already being explored in the clinical setting.
In addition, SOX2 in LSCC was also found to be dependent on another chromatin regulator called EZH2. EZH2 inhibition is already known to downregulate SOX2 expression in triple negative breast cancer, making it an attractive focus of future studies.
New lung squamous cell carcinoma subtype
With their extensive data, the researchers set out to gain a more detailed understanding of the previously identified four molecular subtypes of LSCC. To do this, they carried out multi-omic clustering, which integrates multiple data sets. Surprisingly, this revealed a brand new ‘epithelial to mesenchymal transition enriched’ (EMT-E) LSCC subtype.
The EMT-E subtype showed upregulation of EMT. This is the process of epithelial cells transforming into mesenchymal stem cells, which have the ability to differentiate into multiple cell types. EMT enables initiation of metastasis in cancer, potentially making the EMT-E subtype more aggressive. This subtype also displays upregulated angiogenesis – the formation of new blood vessels – which enables benign tumours to become malignant. However, they also found that EMT-E cells have a high number of cellular pathways involving receptor tyrosine kinase signalling. These could be targeted therapeutically, providing hope for the future.
Immune landscape analysis
Immunotherapy is currently one of the more successful treatment types for LSCC. Despite this, only a minority of patients exhibit any long-term responses. Therefore, characterisation of the LSCC immune landscape is necessary to discover how to improve immunotherapy outcomes.
Immune-related proteogenomic analysis carried out by the study found that many tumours upregulate immune regulation pathways and immunosuppressive mediators. These findings once again highlight potential future therapeutic targets. In addition, the presence of the immunosuppressive mediators provides a possible explanation to why some immunotherapy efforts in LSCC are unsuccessful.
Limitations and future studies
The proteogenomic profiling performed is likely to drive future clinical advances in drug target discovery for LSCC. However, tumour heterogeneity is an important complication to consider when treating cancers, and is an avenue not covered in this study. Additionally, the tumours analysed in this research were primary, and it is often metastatic disease that proves lethal. Further studies exploring these areas will be required to see if the targets discovered here are suitable in alternative conditions.
Nevertheless, the data collected represents a great step forward in the understanding of LSCC. The researchers hope that their detailed proteogenomic landscape can guide further research and support the development of new therapeutic techniques.
Image credit: Photo by National Cancer Institute on Unsplash
