Biomarker Helps Identify Lymphoma Patients with Drug Resistance

Biomarker Helps Identify Lymphoma Patients with Drug Resistance
Lymphoma cancer cell. Coloured scanning electron micrograph (SEM) of a lymphoma cell showing early apoptotic changes. A lymphoma is a cell of the immune system that has become cancerous. The cell becomes immortal and can grow indefinitely. A number of

Research shows that presence of a mutated protein means that patients with activated B-cell diffuse large B-cell lymphomas will almost certainly develop resistance to a drug called ibrutinib, a targeted treatment for the cancer.

The team, a collaboration between researchers at the University of Pennsylvania, Weill Cornell Medical College and Harvard Medical School, found that certain mutations in the BCL10 gene can lead to this drug resistance.

“This is a mechanism of resistance that was previously underappreciated,” said Kojo Elenitoba-Johnson, a professor at the University of Pennsylvania Perelman School of Medicine, who took part in the research. The findings were presented at the 62nd American Society of Hematology Annual Meeting & Exposition.

“Ibrutinib would have been a candidate for such patients, but if they have these BCL10 mutations, another route for treatment should be prioritized.”

There are approximately 7–8 cases of diffuse large B-cell lymphoma per 100,000 people recorded each year in the US and UK.  This type of blood cancer is split into different subtypes depending on the cells it originates in and the activated B-cell subtype is one of the most aggressive with poor survival rates.

The small molecule drug ibrutinib is used to treat various B cell cancers, including the activated B-cell subtype. It binds to a protein that helps B cells survive and is able to destroy cancerous tissue and stop these cells moving around the body.

It is often used to treat diffuse large B-cell lymphoma, including the activated B-cell subtype, but the researchers found that patients with specific BCL10 mutations produce a protein that changes cell signalling in the cancer cells and allows them to circumnavigate the drug’s mechanism of action.

The researchers used mass spectrometry-based proteomic analyses to assess how the mutations in BCL10 were changing the action of the resulting protein. They found that although most mutations did not change the protein’s function, some did and were causing increased activity in a protein complex known as NF-κB, which is involved in the cell response to stress, toxic materials or infections.  Abnormal regulation of NF-κB has also been linked to cancer in previous research.

In this case, the research suggested that the BCL10 mutant protein is circumnavigating the normal cell signalling process, which would make ibrutinib ineffective in these patients.

“Cutting off the signaling up top would be immaterial because this protein has now acquired a new capability that subverts the mechanism by which the drug could effectively act as an inhibitor in lymphomas harboring these mutations,” Elenitoba-Johnson said.

The team believes that these mutant proteins can be used as biomarkers to inform oncologists that another treatment other than ibrutinib is needed for these patients.

“Precision medicine is the goal, where individualized therapy, based on genetics and other factors, lets us treats patients with the right drug for the right disease at the right dose and at the right time,” noted Elenitoba-Johnson. “Identifying these new mechanisms strengthens that approach for patients with this type of lymphoma.”