Why don't JAK Inhibitors reduce the disease burden in Myelofibrosis?
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By MPN Research Foundation Scientific Advisor John Crispino, PhD
With the discovery of JAK2 mutations and the recent approval of Ruxolitinib for individuals with myelofibrosis, there is a great deal of excitement and hope. However, there is also concern that, although the inhibitors are effective at reducing symptoms, they have not yet shown the benefit of reducing the disease burden.
Until recently, the reason why JAK inhibitors are not a more effective therapy has been a mystery. A new study by Ross Levine and colleagues, published in the prestigious journal Nature, provides a novel and compelling explanation for this limitation.
An Important Discovery About How JAK2 Works
Levine discovered that JAK2 mutant cells “persist” in the face of JAK inhibitors; that is, JAK2 mutant cells survive the onslaught of a drug rather than dying, and then re-emerge when the drug is removed. This phenomenon is different from chemical resistance shown by other cancers, where malignant cells acquire genetic changes that make them permanently resistant to a drug.
How do MPN cells achieve persistence if not by genetic means? The explanation seems complex, but is fairly straightforward when one understands how JAK/STAT signaling occurs. In order to understand persistence, one has to recognize that JAK kinases work as normal cell, the dominant form is a “homodimer” in which one JAK2 molecule associates with a second JAK2 molecule. In addition to JAK2, however, there are three other family members (JAK1, JAK3, and TYK2) that could each partner with a single molecule of JAK2 to form a “heterodimer.”
Levine showed that JAK2 mutant cells switch from JAK2 homodimers to JAK2 heterodimers in the face of JAK2 inhibition. The disease persists, because signaling through JAK2 heterodimers is relatively insensitive to JAK inhibitors, including Ruxolitinib.
Toward the Next Generation of Treatments
While there is optimism that Ruxolitinib will prove to increase survival and reduce myelofibrosis, there is also awareness that other drugs, likely to be used in combination with a JAK inhibitor, are needed. Levine demonstrated that persistent cells are sensitive to HSP90 inhibitors, which are under investigation as a new therapy for MPNs.
In addition, he showed that other JAK inhibitors that bind inactive JAK2 (in a manner that is distinct from conventional JAK inhibitors) are able to reduce growth of JAK persistent cells. These latter results provide hope that the next generation of therapeutics will not only improve symptoms, but provide potent reductions in disease burden.