Inhibiting ROCK1/2 when using interferon therapy may be effective in the context of myeloproliferative neoplasms (MPNs), according to research published in Nature Communications.
Interferon therapy is a mainstay of anticancer treatment. These therapies promote immune reactions from patients, and have direct anti-tumoral effects, including growth, survival, and migration blocking. Interferon-alpha, in particular, is used in the MPN setting, particularly in the setting of Philadelphia chromosome–negative disease.
MPNs — which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis — are clonal hematopoietic diseases that may develop into acute myeloid leukemia. Previous research has shown, furthermore, that 19 out of 20 patients with MPN have either a JAK2, CALR, or MPL mutation.
Although inhibitors of JAK2 are approved in MPN, their clinical efficacy is only modest. By contrast, while interferon therapy can be effective in this setting, many patients relapse, though the reasons why are unclear. For this study, researchers explored the mechanisms through which Unc-51-like kinase 1 (ULK1) affects the anticancer effects of interferon among patients with MPN.
Researchers evaluated data from mice and 18 patients with MPN treated with interferon, 9 of whom responded and 9 of whom did not respond to treatment. The authors collected patient peripheral blood for analysis.
Results showed that PKC-delta-dependent phosphorylation of ULK1, which consequently activates p38 MAPK, is an essential element of the anticancer effects of interferon. Increased levels of ULK1 and p38 MAPK were correlated with response to interferon-alpha in evaluated patients.
The authors also showed that ROCK1/2, proteins that interact with ULK1, may be activated during interferon treatment, potentially suppressing responses to therapy. Inhibiting ROCK1/2, which appears to be overexpressed in MPN, may eliminate this issue, according to the researchers.
“These findings support future studies to evaluate the clinical potential of combinations of ROCK inhibitors with PEG-IFN[-alpha] and/or the JAK inhibitor ruxolitinib for the treatment of MPN patients,” the authors wrote in their report.
Saleiro D, Wen JQ, Kosciuczuk EM, et al. Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms. Nat Commun. 2022;13(1):1750. doi:10.1038/s41467-022-29381-7