Advances in targeted medicine have benefited patients with certain kinds of lung cancer, but effective therapies for lung squamous cell carcinomas (LSCCs) remain in short supply. In a study recently published in Cell, Michael Gillette, a proteomics expert at the Broad Institute and Harvard University, and his colleagues scrutinized the molecular landscape of lung cancers to look for new treatment targets for LSCC.1 

To get a clearer picture of the molecular landscape of LSCC, Gillette and colleagues probed nine data types, analyzing DNA, RNA, proteins, and post-translational modifications of more than 100 LSCC tumors. The “proteogenomic portrait” revealed unique therapeutic vulnerabilities for LSCC.

No cancer is good, but lung cancer is particularly deadly. Nearly twice as many people die from lung cancer worldwide as the second most fatal kind of cancer. Genomic discoveries have helped to identify targeted therapies for lung adenocarcinoma, the dominant subtype of lung cancer. But those therapies have not had the same impact on LSCC. 

To determine why, Gillette and colleagues turned to the proteome—the entire complement of proteins expressed by a cell or tissue—with the idea that “if we knew more about the business end of the process, the thing that is closer to phenotype than transcriptional profiling or genetic sequencing, it might give us new insights,” Gillette said.

The ability to predict protein levels from upstream information such as DNA sequences or transcript levels is not precise. There’s a “low to middling level of correlation,” Gillette said. The correlations become worse when considering post-translational modifications, which profoundly alter protein function.

To get a better sense of the LSCC proteome, Gillette and colleagues used mass spectrometry to assess the protein landscape of 108 LSCC tumors and nearly the same number of normal adjacent tissues. They extended the analysis to include acetyl, phospho, and ubiquityl post-translational modifications. 

“That kind of discovery approach is on full display in this paper,” said Matthew Ellis, a translational oncologist at Baylor College of Medicine, who was not involved with the new research.

Then Gillette and colleagues went a step further. The researchers performed similar analyses on lung adenocarcinomas and head and neck squamous cell carcinoma (HNSCC), which shares the same cell type of origin as LSCC.

The comparison revealed that copy number deletions are more frequent in LSCC than in lung adenocarcinoma and HNSCC, and these deletions affect immune regulation in LSCC but not in the other two cancer types.

In some cases, the analyses unveiled likely causes for why therapies that work well for other cancers were not landing with LSCC. Therapies that target the epidermal growth factor receptor (EGFR) protein, for example, have been unsuccessful in treating LSCC. The protein analyses that Gillette and colleagues conducted, however, revealed that EGFR ligands may be a more effective therapeutic target for this cancer type.

“We never want to downplay the importance of DNA and genomic sequencing. It’s done a great deal,” Gillette said. “But it’s an incomplete story, and by moving towards a complete story, there are a lot of insights that truly can have near-term translational impact.”

  1. S. Satpathy et al., “A proteogenomic portrait of lung squamous cell carcinoma,” Cell, 184:4348-71, 2021.