Polr1a, which promotes melanoma metastasis, emerges as a new therapeutic target
Background and Challenges
Melanoma is the most aggressive type of skin cancer, and even after initial treatment, the 5-year survival rate drops to below 20% if metastasis occurs, which is a major challenge. In particular, lung metastasis accounts for half of the causes of death in patients, and existing targeted therapies have limitations in sufficiently blocking the growth mechanism of metastatic cells. Therefore, researchers decided to intensively search for genes that are overexpressed in patients with poor prognosis in order to find genes directly involved in the progression of metastasis. However, most previous screenings were conducted only in vitro, making it easy to miss drivers that function in the actual tissue environment. Therefore, it is necessary to directly confirm the effects of complex cell-to-cell signaling networks and ribosomal biosynthesis in tissues on metastatic ability.
Research Methods and Key Findings
The research team applied CRISPR-based in vivo knockout screening to a mouse model, simultaneously deleting about 200 genes associated with poor prognosis and observing the formation of lung metastasis. As a result of the screening, polymerase I subunit A (Polr1a) was identified as the gene that most strongly increased the frequency of metastasis, and analysis of patient databases also showed that patients with high Polr1a expression had an average survival period of about 12 months shorter. Polr1a-deficient melanoma cells showed significantly reduced motility, invasiveness, and ability to colonize lung tissue, which was interpreted as a result of ribosomal RNA synthesis inhibition affecting the reorganization of the cytoskeleton. Ribo-seq analysis revealed that Polr1a regulates the non-canonical NF-κB pathway, and in particular, it was confirmed that the translation of RelB and p52 proteins decreased. At the same time, melanoma cells treated with the Polr1a inhibitor BMH-21 showed a sharp decrease in non-canonical NF-κB signaling, and the ability to move and invade decreased by more than 60%, and almost no mouse lung metastasis lesions were detected.
Future Significance and Prospects
With the development of new drugs directly targeting Polr1a currently entering the preclinical stage, it is highly likely that a Phase I clinical trial for melanoma patients will begin within the next 2-3 years. This treatment strategy is expected to achieve both metastasis inhibition and immune response promotion by inhibiting the non-canonical NF-κB pathway, and it is considered particularly promising in combination with existing immune checkpoint inhibitors. The global melanoma treatment market is expected to grow at an annual rate of 12% to reach $1 billion by 2025, and Polr1a inhibitors are expected to account for a large share of this market with a differentiated mechanism. In addition, by utilizing the connection between Polr1a and the NF-κB signaling network, it is possible to verify the metastasis inhibition effect in other solid cancers, which may open up a new treatment paradigm for cancer in general. Therefore, researchers and pharmaceutical companies should simultaneously investigate the toxicity profile and long-term effects of Polr1a-based therapeutics and pursue a strategy to accurately select patient populations through the development of personalized biomarkers.
Identification and characterization of novel mechanisms driving melanoma metastases and ways to target them are paramount for the development of effective treatment modalities. Here, we employed in vivo CRISPR knockout screening targeting the genes associated with poor prognosis to identify Polr1a as a potent driver of melanoma metastasis. High Polr1a levels correlate with increased metastasis and reduced survival in patients. Polr1a inhibition suppressed migration, invasion, and the ability of melanoma cells to colonize lungs. Ribo-seq analysis revealed that Polr1a is involved in regulating the non-canonical NF-κB pathway. Indeed, targeting Polr1a decreased levels of RelB and p52 and suppressed non-canonical NF-κB transcriptional activity; this suppression was responsible for the effects of Polr1a on melanoma cell migration. Accordingly, pharmacological inhibition of Polr1/Polr1a suppressed cell migration, tumor growth, and metastases. We discuss the potential utilization of Polr1 inhibitors for neoadjuvant treatment of melanoma.
Melanoma metastasis is a serious problem that cannot be completely suppressed by current treatments, leading to a rapid increase in patient mortality, and in particular, patients with lung metastasis have an average survival period of less than one year. In the past, targeted therapies were stalled due to the failure to accurately identify key genes directly involved in the progression of metastasis, and most screenings were performed only in vitro, failing to reflect the actual tumor microenvironment. This study overcomes the limitations by identifying Polr1a as a key driver of metastasis using a new approach called in vivo CRISPR knockout screening and revealing the connection with the non-canonical NF-κB pathway. This discovery enables the development of new drugs based on Polr1a inhibitors that can simultaneously achieve metastasis inhibition and immune activation, which can create new growth momentum in the melanoma treatment market, which is currently worth $100 million. In the future, Polr1a-targeted therapies are likely to undergo Phase I/II clinical trials and be used in combination with immune checkpoint inhibitors, which will be a turning point in fundamentally changing the paradigm of cancer metastasis treatment within the next five years.