Synthetic Lethality

Synthetic lethality (SL) is a concept first identified in the model genetic system Drosophila melanogaster (fruit fly) and recapitulated in yeast and other organisms. It was suggested as a potential cancer treatment modality nearly 20 years ago (Hartwell et al, 1997) and proof of concept for the approach now exists with the 2014 approval of the PARP inhibitor, Lynparza® (olaparib), as an effective treatment for patients with BRCA 1/2 mutant ovarian cancer. Importantly, this biomarker driven approach to direct therapy to a “BRCA” subset of ovarian cancer patients has resulted in superior response rates and significant progression free survival.

IDEAYA is prosecuting a novel set of drug targets through a tripartite approach that integrates 1) robustness and conservation of SL interactions across different organisms and in human tumor cells, 2) disease relevance of drug target and prevalent loss-of-function mutation in SL partner gene, and 3) ability to drug with a small-molecule therapeutic.

Pre-PARP Inhibitor Treatment

Gene A = BRCA (Biomarker)
Gene B = PARP (Drug Target)

Normal cells harbor wild type Gene A and Gene B. Viable tumor cell harbor mutated Gene A (BRCA).

Post-PARP Inhibitor Treatment

Synthetic Lethality between Gene A (BRCA) and Gene B (PARP) causes cancer cell death.

Normal Cell survives as it does not harbor the BRCA mutation.