Promising ASCO readouts suggest targets in the ATR pathway are lining up behind PARP as the next drivers of “synthetic lethal” cancer killing.
Biomarker and combination strategies presented at the American Society of Clinical Oncology meeting indicate the thinking may need to go beyond simple two-way synthetic lethal interactions like PARP-BRCA, which involve one inhibitor plus one mutation.
ASCO data on the ATR pathway gave fuel to an emerging idea that synthetic lethality combinations can also be created via a drug plus another drug, or even triple combinations of drugs plus mutations.
Once the first PARP inhibitor showed proof of concept, the question became what other pairings could yield new cancer drugs. The four approved PARP inhibitors are marketed to breast and/or ovarian cancer, and are being tested in a growing number of indications, most recently metastatic pancreatic cancer (see “Broadening the PARP Playing Field”; "Lynparza shows PFS benefit of 3.6 months in pancreatic cancer").
The principle of synthetic lethality is that while cancer cells can tolerate or even benefit from losing one regulator of DNA damage repair (DDR), such as BRCA1, simultaneous inhibition of a second DDR protein, such as PARP, causes overwhelming