KIT's ship comes in

Mali et al demonstrate in this issue of Blood that oncogenic KIT alleles can be attacked through their reliance on signaling through the phosphatase SHP2.¹  The importance of aberrant signal transduction in leukemia has long been appreciated. This insight is finally having impact in the clinic, when appropriate tyrosine kinase inhibitors (TKIs) are available.

Activating mutations in KIT are found in systemic mastocytosis and in rare acute myeloid leukemia (AML) cases. KIT mutations in AML are associated with poor prognosis, and inhibition of KIT activity seems warranted. Unfortunately, most oncogenic mutations affect the activation loop of KIT in a way that not only activates its kinase activity but also prevents the binding of first-generation TKIs that might otherwise be used to suppress KIT signaling. Although newer TKIs may be able to address such alleles, the problem of resistance due to mutations in KIT is likely to persist.

One possible solution to this problem is to target KIT indirectly, through normal components that are likely to be invariant among AML patients but are required for KIT to exert its leukemogenic effect. The authors hypothesized that the nonreceptor protein tyrosine phosphatase SHP2 might play such a role. SHP2 is a highly conserved enzyme that is crucial for propagation of positive growth signals in many cell types, including hematopoietic stem cells and myeloid progenitors.^2,3  Hematopoietic malignancies sometimes harbor mutations in PTPN11 (the gene encoding SHP2), but in cases with mutations affecting receptor tyrosine kinases SHP2 plays a supporting role.

Mali et al attempted to inhibit SHP2 using II-B08, a compound they had developed previously.⁴  They found that II-B08 reduced SHP2 phosphorylation and, importantly, strongly attenuated the proliferation and survival conferred by an activated KIT allele (D814V). This effect was not observed in cells lacking SHP2, arguing for at least some specific effects of this compound. They further characterized signaling downstream of c-KIT, and found that a single phosphotyrosine (Y719) is sufficient for assembling complexes consisting of KIT, SHP2, Gab2, and PI3 kinase (PI3K; p85α). Exposure of cells to II-B08 attenuated complex formation and reduced the activation of downstream pathways.

In vivo, II-B08 caused a modest survival benefit in mice transplanted with a cell line transformed by KIT-D814V. Based on their biochemical analysis showing that II-B08 yielded incomplete inhibition of KIT signaling, they added a PI3K inhibitor in conjunction with II-B08. The combination therapy was significantly more effective than either treatment alone. The phenotypes associated in genetic models with complete loss of SHP2 are consistent with II-B08 providing only partial loss of SHP2 function. However, in this case a therapeutic index might be derived from an increased dependence of leukemic cells on high levels of tonic signaling.

There are clear caveats to this early work. The compound II-B08 is in a very early stage of development, and it is likely that its complete spectrum of activity is unknown. Furthermore, the model systems used in this work are several steps removed from patients in the clinic, and more complications may arise if primary leukemia cells are wired differently. Nonetheless, this study supports the potential of phosphatase inhibitors in treating cancer and bolsters the incentive to address this pharmacologically challenging goal.⁵ 

Importantly, this approach may be generalized to malignancies mediated by other receptor mutations. For example, the role of SHP2 in FLT3 signaling makes this work more broadly relevant to AML. Since its first description in Drosophila, SHP2 has been recognized as a critical signal relay protein downstream of multiple mitogenic receptors. Therefore, the demonstration by Mali et al that an early SHP2 inhibitor can be given safely to mammals, and selectively restrict the growth of malignant cells, may open a new front in the battle against oncogenic receptor mutations.