This STAT3-induced 11-gene signature can predict which cancers will respond to synthetic lethal therapies, such as poly ADP-ribose polymerase (PARP) inhibitors that have been successfully used in ovarian and breast cancer. According to the International Agency for Research on Cancer, the global cancer burden in 2020 alone included 19.3 million new cancer cases and nearly 10 million cancer deaths. PARP inhibitors have proven effective in treatments of breast and ovarian cancer arising from a mutation in BRCA genes. Studies indicate that many patients have cancers that respond to PARP inhibitor therapy despite lacking mutations in BRCA genes. However, predicting and therefore identifying patients with cancers that will respond to PARP inhibitors is a major challenge.
Researchers at the University of Florida have discovered the vital role of a known oncogene, STAT3, in inhibiting homologous recombination (HR) repair of DNA, a major mechanism that cancer cells need in order to proliferate. Cancers with BRCA gene mutations also lack HR repair, making them susceptible to PARP inhibitors. The new linkage of STAT3 to HR impairment is a finding that forecasts that many more cancers, beyond breast and ovarian cancers, are likely to be susceptible to PARP inhibitors and synthetic lethal therapies. Thus, the discovery expands the range of cancers that could be treated with synthetic lethal therapies. In addition to this, researchers have identified a STAT3 induced 11-gene signature that can predict which cancers are likely to respond to therapy with PARP inhibitors.
An assay that can determine if synthetic-lethal therapies, such as by PARP inhibitors, will kill a patient’s cancer cells
Cancer cells depend on molecular mechanisms to repair DNA to proliferate. If one mechanism is lost, the cell relies on the remaining mechanisms of DNA repair. Proteins encoded by BRCA genes are critical for homologous recombination (HR) repair, a major type of DNA repair for cancer cells. In breast and ovarian cancers that carry mutations in BRCA1 or BRCA2 genes, HR repair is defective. Synthetic lethal therapies inhibit PARP, an enzyme important for another type of DNA repair, killing the cancer. However, while only 5 to 10 percent of breast and ovarian cancers have a BRCA gene mutation, many more breast, ovarian, and other cancers are susceptible to PARP inhibition, which suggests that something other than the mutation inhibits HR repair. UF researchers have found that a prominent oncogene known to be overactive in two-thirds of human cancers, Signal Transducer and Activator of Transcription 3 (STAT3), inhibits HR repair. In addition, researchers have identified an 11-gene signature downstream of STAT3 that can predict which cancers are likely to respond to therapy with PARP inhibitors. This small gene signature can be developed into a real-time PCR/chip/microarray-based clinical test.
