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 for ovarian cancer patients having tumors with BRCA mutations has resulted in superior response rates and significant progression free survival.

IDEAYA is prosecuting a novel set of drug targets selected through consideration of the robustness and conservation of synthetic lethality interactions across different organisms and in human tumor cells, disease relevance of drug target and prevalent loss-of-function mutation in a synthetic lethality partner gene, and ability to drug the target with a small-molecule therapeutic.

Pre-SL Inhibitor Treatment

Gene A = Biomarker (e.g., BRCA)
Gene B = Drug Target (e.g., PARP)

Normal cells harbor wild type Gene A and Gene B. Tumor cells harbor mutated Gene A (BRCA).

Post-SL Inhibitor Treatment

Synthetic lethality between mutated Gene A (BRCA) and pharmacologically inhibited Gene B (PARP) causes cancer cell death.

Normal Cell survives as it does not harbor Gene A (BRCA) mutation.