A cellular protein called TYK2 plays a key role in tumor development and survival in anaplastic large-cell lymphoma (ALCL), according to a new study. The finding suggests that targeting TYK2 could become a therapeutic strategy to treat these patients.
The research, “Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma,” was published in the journal Leukemia.
Improved diagnostic methods have enabled individual treatment strategies against increasingly smaller, thereby more specific, cancer subcategories. In this effort, cancer researchers have pursued molecular analyses of tumors to discover new therapeutic targets and validate them in tumor models.
However, the small number of patients with rare cancers such as ALCL makes it challenging to validate such findings.
Activation of TYK2 has been reported in ALCL and T-cell acute lymphoblastic leukemia (T-ALL), among other diseases. Mutations in the TYK2 gene have been found in T-ALL cell lines, but little is known about the role of TYK2 in cancer and the proteins it activates.
Aiming to address this gap, the research team from Medical University of Vienna, in Austria, and its collaborators in the U.S., Germany and Singapore, focused on ALCL, an aggressive non-Hodgkin’s T-cell lymphoma.
About half of ALCL patients have a genetic mutation where the ALK and NPM1 genes become fused. These patients can be treated effectively with standard chemotherapy regimens or ALK inhibitors. However, those not showing this molecular pattern have worse prognosis, underscoring the need for new therapeutic options.
Researchers found that ALCL patient samples produce TYK2 regardless of ALK status. And TYK2 activation was associated with the activation of two proteins — STAT1 and STAT3 — involved in gene expression and implicated in tumor development. It also led to the production of MCL1, a protein that prevents cells from dying.
In mouse models of ALCL, depleting TYK2 from immune T-cells significantly delayed tumor onset and increased survival, suggesting that TYK2 is essential for tumor cell survival and growth.
“We were therefore able to regard the TYK2 signals as the Achilles heel of ALCL, since both types of ALCL that we investigated relied on its activity to maintain the essential signal to protect against cell death,” Olaf Merkel, the study’s co-senior author, said in a press release.
“Our data underscore the potential therapeutic importance in ALCL of TYK2 inhibitors,” the scientists wrote.
“We look forward to TYK2 inhibitors, which are currently being developed for treating immunological diseases, being available, since we urgently need better treatments for rare lymphomas,” concluded Lukas Kenner, also a co-senior author of the study.