To outsmart aggressive cancers, scientists need a new approach. They need to turn on tumor suppressor genes and tumor evasion genes which have been deactivated by malignant cells. One of the newest approaches is using synthetic lethality — when two simultaneous genetic events result in cell death. Cells can live when one gene is lost but cannot survive the combined loss of a redundant pathway. With synthetic lethality, scientists are able to exploit this redundant pathway, often by introducing a precision-designed therapeutic.
Synthetic lethality offers new hope for treating cancers that have eluded other forms of therapy, including breast, ovarian, bladder, and pancreatic cancers with specific mutations and deletions, like BRCA (breast cancer gene) mutation and MTAP (methylthioadenosine phosphorylase) deletion. BRCA1 and BRCA2 are tumor suppressor and DNA repair genes. These genes are mutated in many cancers, including 30-40% of familial breast cancer patients and up to 80% of hereditary ovarian cancer patients. To block these genes, the synthetic lethality target is PARP, a DNA repair enzyme that can be chemically inhibited to suppress tumor growth. MTAP, another enzyme important to cell function that is deficient in many cancers, can be targeted through MAT2A (methionine adenosyltransferase 2A), an enzyme that plays an essential role in cell function and survival
as the primary producer of S-adenosylmethionine (SAM). WRN (Werner Helicase), another enzyme active in DNA repair and transcription, has also been discovered as a promising synthetic lethality target for colorectal and other cancers.
In order to find new synthetic lethality targets and develop novel therapeutics, scientists are relying on the latest technologies, including CRISPR gene-editing and artificial intelligence (AI). Many big pharma companies and biotech startups are jumping into the race.