Researchers have identified a lung squamous cell cancer (LUSC) oncogene called BCL11A that has the potential for drug targeting, according to a study published in Nature Communications.
“Platinum-based chemotherapy remains the first-line treatment for LUSC, and although the recent FDA approval of necitumumab in combination with platinum-based chemotherapy for metastatic LUSC has shown positive signs, a great deal of work still needs to be done in this field,” wrote the authors, led by Kyren A. Lazarus, PhD, Department of Pharmacology, University of Cambridge, Cambridge, UK.
The development of LUSC is still puzzling to researchers.
“Until now, our molecular understanding of this process was limited,” Dr. Lazarus said. “Our research has revealed a major piece of this puzzle, which we are now actively trying to make new drugs against.”
Globally, LUSC results in 400,000 deaths per year, with few targeted therapies available to fight the disease. During the past 40 years, lung cancer survival in general has been low compared with other types of cancer, which is in part due to a paucity of targeted therapies.
LUSC arises from basal cells in the main and central airways. At the molecular level, LUSC has not been studied extensively. However, amplifications of Sex Determining Region Y (SRY)-Box 2 patients (SOX2) exist in 70% to 80% of cases.
The team analyzed cancer genomics datasets and discovered that BCL11A is upregulated in LUSC. Notably, BCL11A is not upregulated in lung adenocarcinoma (LUAD), another broad histologic category of non-small cell lung cancer.
LUAD arises from secretory epithelial cells in the lung and has been robustly characterized from a molecular standpoint. Furthermore, targeted therapies have been developed for LUAD.
The investigators experimentally showed that nonphysiological levels of BCL11A in vitro and in vivo facilitate squamous-like phenotypes, while its knockdown stops tumor formation. Of note, the they used Cre-inducible mouse model that permitted the overexpression of BCL11A.
The team found that BCL11A is transcriptionally regulated by SOX2, and BCL11A and SOX2 together regulate various transcription and key epigenetic factors, including SETD8. They showed that the inhibition of SETD8 stopped LUSC growth, yielding selective effects in LUSC vs LUAD cells.
The researchers noted that SETD8 can potentially be targeted with drugs, opening the door to new treatments.
“By disrupting the BCL11A-SOX2 transcriptional program, our results provide a potential future framework for tackling the unmet clinical need for LUSC patients,” the researchers wrote.
The investigators explained that they are currently developing small molecules to block BCL11A in LUSC tumor cells. They are trying to interfere with key interactions that BCL11A exhibits with other proteins.
“Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A–SOX2 transcriptional program as a novel candidate for drug development,” the authors concluded.