Cancer treatment faces the challenge of eliminating diseased cells without harming healthy tissues. Traditional therapies often struggle with this selectivity, leading to unwanted side effects. Scientific research seeks to uncover unique vulnerabilities within cancer cells that can be specifically targeted. This approach aims to develop more effective treatments that cause less damage to the body.
Understanding Synthetic Lethality
The concept of synthetic lethality describes a genetic interaction where the combination of two genetic changes results in cell death, even though either change alone is not lethal. Cells typically possess backup mechanisms, or parallel pathways, that can compensate if one pathway is compromised. This redundancy ensures cell survival under normal circumstances.
In the context of cancer, this principle becomes therapeutically relevant. Cancer cells often harbor a pre-existing genetic defect or mutation that disrupts one of these cellular pathways. While this single defect might not be enough to kill the cancer cell, it forces the cell to rely more heavily on its compensatory pathways for survival.
Scientists then search for a second genetic alteration or a drug that inactivates the other pathway. When both pathways are simultaneously compromised, the cancer cell loses its ability to survive and dies, while healthy cells with intact pathways remain unaffected. This targeted approach exploits the unique genetic makeup of cancer cells, offering a path to selective elimination.
How Synthetic Lethal Screens Work
Identifying synthetic lethal interactions involves systematic, large-scale testing. Researchers employ “screens” to evaluate thousands of gene combinations or drug interactions in a controlled laboratory setting. The goal is to uncover pairs of genetic alterations or a genetic alteration combined with a chemical compound that specifically induces cell death in cancer cells.
One common method involves genetic perturbation techniques like RNA interference (RNAi) or CRISPR-Cas9 technology. RNAi can “knock down” or reduce the expression of specific genes, while CRISPR-Cas9 can precisely “knock out” or eliminate gene function. By systematically altering genes in cancer cells, scientists can observe which alterations, when combined with a pre-existing cancer-specific defect, lead to cell death.
These screens often use either a “forward” or “reverse” approach. A forward screen examines diverse cancer cell lines to find common vulnerabilities. A reverse screen involves creating isogenic cell lines, where a specific cancer-related mutation is introduced into otherwise normal cells, allowing direct comparison of vulnerabilities. High-throughput drug screening complements genetic screens by testing vast libraries of chemical compounds to identify those that are synthetically lethal with specific cancer cell defects.
Real-World Applications
The concept of synthetic lethality has transformed cancer treatment, leading to the development of targeted therapies. A prominent example is the use of PARP inhibitors for cancers with mutations in the BRCA1 or BRCA2 genes. BRCA1 and BRCA2 proteins are involved in a major DNA repair pathway called homologous recombination repair (HRR).
When BRCA1 or BRCA2 genes are mutated, as often occurs in certain breast, ovarian, pancreatic, and prostate cancers, the HRR pathway is impaired. These cancer cells then become highly reliant on an alternative DNA repair pathway, primarily managed by the PARP (Poly ADP-ribose polymerase) protein. PARP inhibitors, such as olaparib, rucaparib, and niraparib, block this compensatory PARP pathway.
By inhibiting PARP, these drugs prevent the cancer cells from repairing DNA damage, which accumulates to lethal levels. Healthy cells, possessing functional BRCA genes and an intact HRR pathway, can still repair DNA damage effectively, thus remaining unharmed by PARP inhibitors. This selective toxicity highlights the practical power of synthetic lethality in treating specific types of cancer.