A type of chronic leukemia can simmer for many years. Some patients may need treatment to manage this type of blood cancer — called myeloproliferative neoplasms (MPN) — while others may go through long periods of watchful waiting. But for a small percentage of patients, the slower paced disease can transform into an aggressive cancer, called secondary acute myeloid leukemia, that has few effective treatment options. Little has been known about how this transformation takes place. But now, researchers at Washington University School of Medicine in St. Louis have identified an important transition point in the shift from chronic to aggressive leukemia. They have shown that blocking a key protein in the transition pathway, called DUSP6, prevents this dangerous disease progression in mice with models of the disease and in mice with tumors sampled from human patients. The research appears Dec. 29 in the journal Nature Cancer.
The study suggests that inhibiting this key transition molecule helps overcome the resistance that these cancers often develop to JAK2 inhibitors, the therapy typically used to treat them. JAK2 inhibitors are an anti-inflammatory therapy also used to treat rheumatoid arthritis. The researchers conducted a deep dive into the genetics of these tumors, both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors. The DUSP6 gene stood out as highly expressed in the 40 patients whose tumors were analyzed in this study. Using genetic techniques to delete the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer. The researchers also tested a drug compound that inhibits DUSP6 and found that the compound (only available for lab research), stopped progression of the chronic disease to the aggressive disease in two different mouse models of the cancer and in mice with human tumors sampled from patients.
Reducing DUSP6 levels both genetically and with a drug also reduced inflammation in these models. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 kinase (Rsk1) and the JAK-STAT signaling module while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which was identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across mouse models with JAK2 V617F or MPL W515L mutations and AML xenografts, without inducing toxicity in healthy controls. Since the drug that inhibits DUSP6 is not available for human clinical trials, scientists are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6.
There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1. Ribosomal kinase S6 (Rsk1) of the MAPK modiule has been shown to play a key role in cellular resistance to chemotherapeutic drugs. Furthermore, it drives part of the mitogenic effects of growth factors in both normal and tumor cells. The team is interested in investigating these drugs for their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition. Inhibitors against Rsk1 and related Rsk2 have been developed and applied to basic science to unravel downstream signaling of MAPKs. Examples are SL-101, BRD7389 and PF4708671. However PMD-026 is the first identified RSK1 inhibitor that may be clinically relevant that is in phase 1 clinical trials for patients with breast cancer, so scientists are hopeful our work provides a promising foundation for developing a new treatment strategy for patients with this chronic blood cancer.
Stephen T Oh, MD, PhD, senior author, associate professor of medicine and co-director of the Division of Hematology, Washington University School of Medicine in St. Louis, explained: “Secondary acute myeloid leukemia has a grim prognosis. Almost every patient who develops acute leukemia after a history of myeloproliferative neoplasms will die from the disease. Therefore, a major focus of our research is to better understand this conversion from chronic to aggressive disease and to develop better therapies and, hopefully, prevention strategies for these patients. They are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy. A future clinical trial might enroll myeloproliferative neoplasm patients who are taking JAK2 inhibitors and, despite that, show evidence of their disease worsening. At that point, we might add the type of RSK inhibitor that’s now in trials to their therapy to see if that helps block progression of the disease into an aggressive secondary acute myeloid leukemia.”
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochiemistry.
Advised in this website
Kong T, Laranjeira AB et al. Nat Cancer 2022 Dec 29.
Ushijima M et al. Cencer Sic. 2022; 113(5):1731-38.
Limberger T et al. Mol Cancer 2022 Mar; 21(1):89.
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