Lung cancer is one of the cancers with the lowest survival rates. What’s even more frustrating is that in the past four decades, although the overall survival rate of cancer patients has more than doubled, the survival rate of lung cancer patients has hardly improved. Currently only 5% of lung cancer patients have a survival period of more than 10 years. One of the reasons for this dilemma is the lack of therapeutic targets for lung cancer in the industry, but scientists from the University of Cambridge in the UK may change this.
Lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for approximately 85% of all lung cancer cases, which is subdivided into four categories based on pathology including lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell carcinoma, and undifferentiated NSCLC. Squamous cell carcinoma accounts for 25% to 30% of all NSCLC cases. At the cellular level, LUAD tends to originate from secretory epithelial cells in the lung, whereas LUSC typically originates from basal cells located in the primary and central airways. At the molecular level, LUAD is known to have mutations of epidermal growth factor receptor (EGFR), V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and anaplastic lymphoma receptor tyrosine kinase (ALK). In LUSC, 70-80% of patients have an expansion of sex determination region Y (SRY)-Box 2 (SOX2). Unlike LUAD, there is currently no confirmed therapeutic target for LUSC, so platinum-based chemotherapy remains the first-line treatment for LUSC.
In one study, scientists at the University of Cambridge found that a protein called BCL11A is highly expressed in LUSC. The high expression of BCL11A at a non-physiological level promotes a squamous phenotype in a mouse model or cell culture and eliminates the formation of xenograft tumors after knockout. The researchers further revealed that BCL11A is regulated by the transcriptional regulation of SOX2 and is required for its carcinogenic function. It is finally confirmed that inhibition of SETD8, a transcription factor regulated by BCL11A and SOX2, selectively inhibits LUSC growth, making SETD8 a potential LUSC therapeutic target. This result was published in the recent Nature Communication.
The article reports that the researchers first analyzed the expression of LUSC and LUAD transcription factors in cancer genomic profiling (TCGA) and found that BCL11A and SOX2 were specifically highly expressed in LUSC, but not in LUAD. Next, the researchers used small hairpin RNA (shRNA) technology to knock out the BCL11A gene in LUSC cell lines, and found that LUSC cells lost the ability to form xenograft tumors in mice. At the same time, the expression level of BCL11A was found increasing in mice and the 3D cultured similar organs of basal cells ( the source of LUSC cancer cells), leading to abnormal morphological changes in airway cells and tissues and proving that the BCL11A gene is an oncogene of LUSC.
On the other hand, LUSC cell lines that knocked out SOX-2 using shRNA also showed similar loss of tumor-forming ability, accompanied by a significant decrease in the expression level of BCL11A gene, and increased expression of BCL11A in these cell lines. Levels partially improve their ability to form tumors. This result indicates that BCL11A plays a partial regulatory role in the transcription factor changes brought about by the SOX-2 signaling pathway. Further chromatin immunoprecipitation sequence analysis and quantitative PCR analysis demonstrated a strong direct regulatory relationship between BCL11A gene and SOX-2 gene, and co-immunoprecipitation experiments demonstrated a direct interaction between BCL11A protein and SOX-2 protein.
Next, the researchers used doxycycline-induced shRNA knock-out technology to screen for possible therapeutic targets of the BCL11A/SOX2 signaling pathway and found that knocking out the SETD8 gene specifically affects the tumorigenic capacity of LUSC cell lines. This shows that SETD-8 may be a therapeutic target for LUSC. SETD8 is a member of the SET domain family that catalyzes the monomethylation of histone H4 Lys20, while histone H4 is involved in the recruitment of signaling proteins or chromatin modifications. In addition, SETD8 plays a role in maintaining skin differentiation and is dysregulated in a variety of cancer types. Finally, the small molecule inhibitor NSC663284 inhibits SETD-8, selectively kills LUSC cell lines, and makes LUSC cell lines more sensitive to cisplatin chemotherapy, demonstrating the potential of this target.
Dr. Kyren Lazarus, research assistant at the University of Cambridge, the first author of the article, said: “Our research reveals an important part of this problem (the molecular mechanisms and therapeutic targets of LUSC), and we are now actively trying to make new drugs.”
Dr. Walid Khaled, the corresponding author, a lecturer in the Department of Pharmacology at the University of Cambridge, said: “The development of targeted therapies is a real opportunity to improve the patient’s treatment prospects. Thanks to the UK Drug Research Center’s new drug research and development funding, we are working on the development of small molecule drugs, Specific blocking of BCL11A in LUSC cells disrupts key interactions between BCL11A and other proteins. We are working closely with colleagues in the Department of Biochemistry at Cambridge University and CRUK Beatson Drug Development to achieve this goal.”
Professor Karen Vousden, chief scientist at the Centre for Cancer Research in the United Kingdom, said: “The identification of potential drug targets is a critical stage in the early stages of precision medicine. While much remains to be done to improve treatment of patients, it is the basis for achieving this. We look forward to seeing how this discovery continues along the R&D pipeline.”