Drug resistance: identified a new key mechanism in the treatment of B-cell lymphomas

The Lymphoma Genomics Laboratory, directed by Prof. Francesco Bertoni at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+), identified a new mechanism behind the resistance to BTK and PI3K inhibitors used in the treatment of patients with follicular lymphoma, mantle cell lymphoma and marginal zone lymphoma.

One of the causes of the failure of anticancer therapy in treating lymphomas is the development of drug resistance, which implies a decrease in the therapeutic efficacy of a given drug. It is, therefore, fundamental to study the mechanisms behind these resistances to optimize the use of the drugs in the treatment of patients. Examples are drugs such as ibrutinib or zanubrutinib, molecules that target the Bruton Tyrosine Kinase (BTK), or idelalisib, targeting a phosphoinositide 3-kinase, approved by the U.S. Food and Drug Administration (FDA) and SwissMedic for the treatment of various populations of patients with lymphoma or chronic lymphocytic leukemia. Although their efficacy, the exposure to these agents generate the development of drug resistance, restricting their use.

The discovery

In a study published in Molecular Cancer Therapeutics, the Lymphoma Genomics research group identified new factors responsible for the resistance to the BTK and PI3K inhibitors.
In particular, Alberto Arribas, Sara Napoli and colleagues developed a cellular model that mimicked the BTK and PIK3 inhibitors resistance observed in marginal zone lymphoma patients. To this aim, they kept the Karpas-1718 lymphoma cell line under continuous exposure to idelalisib, thus desensitizing the cells and developing drug resistance.

A detailed analysis of idelalisib-resistant cells allowed the researchers to identify the factors (ERBB4 and its ligands HBEGF and NRG2) responsible for the drug resistance and how to tackle them.

Experiments confirmed the role of this axis in blocking the antitumor effects of BTK/PI3K inhibitors.

By using targeted treatments against the identified factors, the researchers were able to overcome the resistance, thus making the cells again sensitive to BTK and PI3K inhibitors.

These findings were confirmed on clinical specimens, highlighting ERBB4 overexpression as a novel resistance mechanism to BTK and PI3K inhibitors, with potential for targeted interventions to restore sensitivity.

In conclusion, thanks to the novel model of idelalisib-resistance in Karpas-1718 cells, the researchers identified the factors responsible for the drug resistance and demonstrated that targeted treatments against these factors can improve the anti-tumor activity of BTK and PI3K inhibitors.

Link: https://aacrjournals.org/mct/article-abstract/doi/10.1158/1535-7163.MCT-23-0068/731515/ERBB4-Mediated-Signaling-Is-a-Mediator-of?redirectedFrom=fulltext