8:07 PM
Jun 06, 2019
 |  BC Innovations  |  Targets & Mechanisms

Following PARP, ATR axis next in line to expand synthetic lethal drug class

As companies search for the successor to PARP, the ATR axis becomes a key contender

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 genetic damage that triggers cell death.

Scores of preclinical studies have characterized synthetic lethal DDR interactions beyond PARP and BRCA, including the replication stress sensor ATR and its downstream targets Chk1 and WEE1 (see "Meeting the Burden").

At ASCO, Bayer AG presented data from a first-in-human Phase I trial of its ATR inhibitor BAY-1895344, in which all responders in the dose-escalation cohort were retrospectively shown to lack function of the kinase ATM. The findings support a long-standing hypothesis from preclinical studies that ATM acts as ATR’s synthetic lethal partner. These patients survived for a year or more.

"We see an opportunity for ATR to be linked directly to patient populations."

Michael Zinda, Repare Therapeutics

Other companies developing ATR inhibitors are encouraged by the results, which could be leveraged for a biomarker strategy in patient recruitment. "We see an opportunity for ATR to be linked directly to patient populations," said Michael Zinda, CSO of Repare Therapeutics Inc., a preclinical-stage synthetic lethality company founded by Versant Ventures in 2016.

Presentations on compounds from KGaA, Sierra Oncology Inc. and AstraZeneca plc provided evidence for using different combinations of mutations and...

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