New research from Memorial Sloan Kettering Cancer Center (MSK) uncovers why some leukemia patients stop responding to promising new drugs; examines how bone's hardness shapes the immune battle against metastasis; shows how a telehealth tobacco treatment program helps cancer patients quit smoking; creates the first atomic-level images of a key phosphate transporter that could inform treatment of ovarian cancer and kidney disease; finds Medicare Advantage patients with cancer receive optimal treatment at lower cost; and studies how much tissue surgeons should remove for tumor–related epilepsy.
Why some leukemia patients stop responding to promising new drugs
For years, doctors have treated chronic lymphocytic leukemia (CLL) with drugs called BTK inhibitors, which block a protein that helps cancer cells survive and multiply. Unfortunately, many patients eventually develop resistance, and the drugs stop working.
Newer drugs called BTK degraders were designed to overcome this problem by destroying, rather than blocking, the BTK protein. Early clinical trials have shown promising results, with response rates exceeding 80% in patients who have failed other treatments. But with these drugs, too, patients may eventually develop resistance.
In a recent study led by MSK scientists, researchers analyzed samples from CLL patients treated with the BTK degraders zelebrudomide or bexobrutideg. The team, including leukemia specialist Meghan Thompson, MD , discovered that when these newer drugs stopped working, a genetic mutation called BTK A428D was present in some of the patients' tumors. Importantly, the team found this mutation existed at low levels before treatment even began, and that by killing off normal cancer cells, BTK degraders inadvertently gave the BTK A428D cells room to grow and take over.
After learning the mechanism by which this takeover occurs, further research suggested a possible way around it: An existing leukemia drug called venetoclax could be combined with BTK degraders to eliminate cells both with and without the BTC A428D mutation. Laboratory experiments in cancer cells confirmed this combination worked.
"Our discovery about a key resistance mechanism in CLL cells has suggested a new approach that may eventually benefit patients," says physician-scientist and co-first author Quinlan Sievers, MD, PhD, a member of MSK's Lymphoma Service and the Omar Abdel-Wahab Llab in the Sloan Kettering Institute. "Based on these findings, we are hoping to launch a clinical trial soon."
