A protein called AMBRA1 may be to blame for tumor resistance to CDK4/6 inhibitors, according to results from international teams of researchers that were reported in Nature.

Using data collected from the Cancer Genome Atlas, the researchers found that low levels of AMBRA1 were a marker of poor outcomes for patients with several cancer types. To identify why, they implanted human lymphoma cells that lacked AMBRA1 into mice and found that the resulting tumors grew much larger and faster than those derived from cells with intact AMBRA1. They also found that the tumors were resistant to CDK4/6 inhibitors because loss of AMBRA1 triggers D-type cyclins to bind to and activate CDK2 in addition to CDK4/6. Finally, they found that blocking another protein, CHK1 (which helps inhibit cell division during replication stress) in cells without AMBRA1 makes cells unable to stop dividing and produces apoptosis.

“AMBRA1 could potentially be used as a biomarker to determine whether a patient will respond to CDK4/6 inhibitors,” the study authors said. They added that “loss of AMBRA1 may also be a vulnerability that could potentially be exploited in cancer treatments. A particular exciting possibility is that CHK1 inhibitors could be used to treat CDK4/6 inhibitor-resistant tumors that have low levels of AMBRA1.”

The researchers are planning additional studies into AMBRA1’s implications for cancer treatment and outcomes.