Potential targets to treat squamous cell lung cancer

Many potential targets for squamous cell lung cancer (SCLC) have been identified by The Cancer Genome Atlas (TCGA). The study was published in Nature, and involved a team of researchers from throughout the United States, plus the British Columbia Cancer Agency in Vancouver, British Columbia, Canada.

Squamous cell lung cancer kills more people each year than breast, colorectal, or prostate cancer, and it is second only to lung adenocarcinoma in the number of deaths it causes. Unlike erlotinib and gefitinib for lung adenocarcinoma, no current treatments for squamous cell lung cancer are aimed at the specific genetic alterations that drive it.

“When we see lung cancer patients, it's almost a double standard. If you have lung adenocarcinoma, we can offer you molecular testing, we can put you in trials, we can put you on some targeted drugs,” said Peter S. Hammerman, a co-chair of the paper's writing and analysis committee, an associated researcher at the Broad, a member of the thoracic oncology program, and instructor at Dana-Farber Cancer Institute and Harvard Medical School. “If you have squamous cell lung cancer, you get the same treatment today you got 10 years ago, which is no more effective than it was 10 years ago. We're just starting to see the first glimmers of hope in squamous cell lung cancer. This paper takes us to the next level in terms of identifying a number of potentially interesting targets to work on.”

The scientists of TCGA used multiple large-scale approaches to highlight key molecular defects, including sequencing the protein-coding segments of the genomes of 178 squamous cell carcinoma tumors and normal tissue from the same patients, sequencing whole genomes of 19 tumor and normal tissue pairs, and mapping a diverse catalog of genomic alterations like rearrangements of chromosomes and other structural changes in regions of the genome.

Possible targets that were identified include the TP53 gene, the CDKN2A gene, three families of tyrosine kinase inhibitors (TKIs), and genomic alterations in signalling pathways. Many of these are already being investigated in other cancers, and all offer opportunities for targeted treatments for squamous cell lung cancer. 

Strikingly, mutations in the HLA-A gene, which direct the ability of the immune system to distinguish between self and nonself, were found. This the first cancer in which HLA-A mutations were found. Matthew Meyerson, MD, PhD, co-leader of the project within TCGA, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School explained, “To our knowledge, this is the first example of a tumor that has a genomic mechanism for evading an immune response. This may be important in understanding the immune response to squamous cell carcinoma and also in envisioning how immune-regulatory therapy might be used for this disease.”

Interestingly, squamous cell lung cancer was found to share many mutations with head and neck squamous cell carcinomas. This finding supports the emerging body of evidence that genetics are more appropriate to classify cancers instead of the primary organ affected.
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