Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia Public Deposited

This dissertation presents novel evidence that PTPN11 is activated by an upstream kinase, TNK2. PTPN11-mutant JMML and AML primary patient cells have displayed significant sensitivity to TNK2 inhibition by dasatinib. My research has revealed that PTPN11 and TNK2 interact directly, allowing for TNK2-dependent phosphorylation of PTPN11. There is a subsequent PTPN11-dependent dephosphorylation of TNK2, suggesting a tightly coupled regulatory signaling loop. Consequent to increased PTPN11 phosphorylation, co-expression of TNK2 and mutant PTPN11 synergistically increases MAP kinase proliferative signaling and mouse bone marrow colony formation. These increases can be significantly blocked with chemical inhibition of TNK2. Clinically, a patient with recurrent JMML who was treated with dasatinib had a therapeutic response. Collectively, these data indicate TNK2 as a promising target for PTPN11-mutant cancers.

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