Lymphomas: new model developed at the IOR against drug resistance
Institutional Communication Service
9 May 2022
The Lymphoma Genomics group, 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 the drug idelalisib, used in the treatment of patients with follicular lymphoma and marginal zone lymphoma.
One of the causes of failure of anticancer therapy in the treatment of lymphomas is the development of drug resistance, which implies a decrease in the therapeutic efficacy of a given drug. This is the case for the drug "idelalisib", used to treat patients with follicular lymphoma, chronic lymphatic leukemia and marginal zone lymphoma (MZL) and which received the approval by both the U.S. Food and Drug Administration (FDA) and SwissMedic. However, although its efficacy, idelalisib generates the development of drug resistance, restricting its use. It is therefore fundamental to study the mechanisms behind these resistances in order to optimize the use of idelalisib in the treatment of patients.
In a study published in Haematologica, an important medical journal, the Lymphoma Genomics group, 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 the drug idelalisib (secondary resistance to PI3K inhibitors, the group of drugs to which idelalisib belongs) making drug-resistant cells sensitive to the drug in question.
In particular, Alberto Arribas, Sara Napoli and colleagues developed a cellular model that mimicked the PIK3 inhibitors resistance observed in MZL patients. To this aim, they kept the VL51 lymphoma cell line under continuous exposure to idelalisib for six months, thus desensitizing the cells and developing drug resistance.
A detailed analysis of idelalisib-resistance cells allowed the researchers to identify which factors were responsible for the drug resistance, and how to tackle them.
By using targeted treatments against the identified factors, the researchers were able to overcome the resistance, thus making the cells again sensitive to idelalisib.
These findings were confirmed in additional cellular lymphoma models and on clinical specimens. In addition to idelalisib, VL51 cells developed resistance to other important PI3K inhibitors such as copanlisib, duvelisib, and umbralisib.
In conclusion, thanks to the novel model of idelalisib-resistance in VL51 cells, the researchers identified the factors responsible for the resistance, and demonstrated that targeted treatments against these factors are able to improve the anti-tumor activity of PI3K inhibitors. Such pharmacological approaches will be tested in clinical trials in patients affected by MZL.
Link to the original publication: https://haematologica.org/article/view/haematol.2021.279957