Acute Myeloid Leukemia (AML) is caused by a variety of genetic aberrations; FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in AML at a frequency of 30%, determining a poor prognosis with high rates of relapse. FLT3 inhibitors used as monotherapy caused initial remission but ended in disappointing final results with relapses emerging in a short time. Studies aimed at elucidating the mechanism of resistance showed that it is due not only to additional mutations in FLT3 but also to development of clones with non-related mutations (for example involving the RAS pathway). Recent studies suggest that a possible strategy is to combine multiple approaches targeting different adaptive pathways, one of the most promising being to combine FLT3 inhibitors with inhibitors of the anti-apoptotic protein bcl-2. However, also in this case preliminary data suggest that FLT3-ITD+ AML cells are able to develop resistance.
We set up a therapeutic strategy based on the induction of ER and oxidative stress that shows cytotoxic activity against FLT3-ITD+ AML, either cell lines and primary blasts isolated from patients, mediated by generation of oxidative stress and by impairment of the adaptive response to ER stress. It relies on the combination of low doses of the differentiating agent retinoic acid (RA), the ER stress inducer tunicamycin (Tm) and the oxidative stress inducer arsenic trioxide (ATO) and importantly does not show toxicity on normal hematopoietic progenitors treated ex vivo. More recently, to facilitate possible translational applications, we substituted Tm with the proteasome inhibitor bortezomib (Btz) to induce ER stress and alteration of proteostasis, obtaining similar results. Indeed RA and ATO are employed in clinical practice for acute promyelocytic leukemia and Btz for multiple myeloma and mantle cell lymphoma. Here we propose to exploit the combination RBA to overcome FLT3-ITD AML resistance to FLT3 or bcl-2 inhibitors.
