Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms

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Project Summary/Abstract Classical myeloproliferative neoplasms (MPNs) are blood disorders that affect about 300,000 people in the U.S. Blood clotting complications and bone marrow failure can cause death, as can the development of an incurable leukemia. Curative therapy by stem cell transplant is rarely possible. Aberrant regulation of a protein called JAK2 drives these disorders, and while JAK2 inhibitors improve MPN patient symptoms they do not induce remission, with inherent drug resistance being a major clinical bottleneck. Our recent studies suggest a protein called SHP2 plays a unique role in the response of MPN cells to the FDA-approved JAK inhibitor ruxolitinib. Therapeutically targeting SHP2 is now possible following the recent development of drugs that function as molecular glue to keep SHP2 stuck in an inactive state. The upfront survival of MPN cells in the face of ruxolitinib treatment is a form of drug resistance called persistence. Our current studies show that ruxolitinib persistent cells are more sensitive to SHP2 inhibition than cells that have never been exposed to ruxolitinib. In the latter cells ruxolitinib inhibits JAK2-dependent signals including STAT and ERK proteins. However, ERK rapidly becomes re-activated even while ruxolitinib is still present. We have observed that SHP2 inhibition blocks this re-activation of ERK. Since ERK can promote cell growth/survival, it is possible that altered SHP2 regulation during ruxolitinib treatment leads to cell survival. Interestingly, the activation states of proteins that mediate JAK2 signaling respond differently to SHP2 inhibition in persistent cells, suggesting cell signaling during ruxolitinib persistence is in a re-wired state. This may explain our observations that SHP2 inhibition can prevent a ruxolitinib persistent state. Thus, SHP2 may provide a vulnerability that can be exploited to improve MPN therapy, which is further supported by our observations that SHP2 inhibition can antagonize disease in an MPN mouse model and can improve the inhibitory effect of ruxolitinib on cells from MPN patients. The major objective of this application is to determine the extent to which SHP2 inhibition overcomes barriers of current anti-JAK2 MPN therapy. The central hypothesis is that targeting SHP2 will thwart the development of JAK2 inhibitor persistence, which is observed in MPN patients. We will utilize cellular, genetic, and biological approaches, including mouse models and cells from MPN patients in our studies. Experiments in aim 1 will determine mechanistic details by which SHP2 inhibition sensitizes MPN cells to JAK2 inhibition; in aim 2 will assess the role of SHP2 in drug persistence; and in aim 3 will determine the molecular basis/consequences of altered SHP2 signaling in response to ruxolitinib, which has potential to help develop new therapeutic approaches based on our novel observations. Our studies are innovative because the unique role of SHP2 in response to JAK2 inhibitor treatment is completely unknown and utilizing SHP2 as a therapeutic target in these MPNs has never been tested. Our studies could contribute to the development of effective therapies for the 300,000 people in the U.S. who suffer with an MPN.