Rational for targeting the hedgehog signalling pathway in acute myeloid leukemia with FLT3 mutation

The FLT3 gene is frequently altered in acute myeloid leukemia (AML) and represents a hallmark of adverse prognosis (1). FLT3-ITD mutation induces constitutive tyrosine kinase activity of the receptor which is located in the endoplasmic reticulum (ER) where it activates STAT5. Clinical trials using FLT3 tyrosine kinase inhibitors (TKI) as monotherapy in AML patients with FLT3 mutation show clinical activity but failed to demonstrate long lasting remissions. Combining FLT3 TKI to vidaza, an hypomethylating agent, demonstrated improved activity and results from the ALLIANCE study which randomized the addition of midostaurin to standard chemotherapy at diagnosis showed a significant improvement in the 5-year overall survival in the combination therapy (2). However, the use of FLT3 TKI led to the identification of resistance mechanisms: (I) the overexpression of oncogenic kinases such as SYK, the AXL receptor tyrosine kinase and the PIM kinases; (II) the gradually increasing levels of FLT3-ligand occurring after repeated cycles of chemotherapy that impair the ability of TKI to inhibit FLT3-ITD activity; (III) the bone marrow microenvironment (BMM) which secretes molecules and generates cellular interactions reported as cytoprotective toward AML cells treated with TKI; (IV) the appearance of acquired mutations in the FLT3-ITD allele that frequently occur within the kinase domain and confer TKI resistance (3)