Mechanisms of resistance to FLT3 inhibitors

Abstract

The success of the small molecule tyrosine kinase receptor inhibitor (TKI) imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia (CML) constitutes an eminent paradigm shift advocating the rational design of cancer therapeutics specifically targeting the transformation events that drive tumorigenicity. In acute myeloid leukemias (AMLs), the most frequent identified transforming events are activating mutations in the FLT3 receptor tyrosine kinase that constitutively activate survival and proliferation pathways. FLT3 TKIs that are in various phases of clinical trials are showing some initial promise. However, primary and secondary acquired resistance stands to severely compromise long-term and durable efficacy of these inhibitors as a therapeutic strategy. Here, we discuss the mechanisms of resistance to FLT3 inhibitors and possible strategies to overcome resistance through closer examination of the events of leukemogenesis and design of combination therapy.

Fig. 1

Major mechanisms and future targets for AML resistant to therapy with FLT3 TKIs. (1) Normally, ITD mutations in the juxtamembrane domain and point mutations in the tyrosine kinase domains (TKD) lock the receptor into an active conformation. Constitutively activated FLT3 activates downstream signaling pathways including PI3K/Akt, MAPKK and STAT5a which lead to continued cell proliferation and survival. (2) Alternate upstream mechanisms that result in activation of the same downstream pathways activated by FLT3 that would not be inhibited by FLT3 inhibitors (e.g., N-Ras). (3) Alternate pathways completely exclusive of FLT3 and downstream FLT3 effector pathways that also lead to transcription of products that allow for continued cell proliferation and survival (e.g., BCL2, NF-κB, etc.). (4) Drug efflux and other mechanisms that reduce overall intracellular drug concentrations. (5) The microenvironmental niche of blasts, first pass drug induction/metabolism, high drug-protein binding resulting in lower free drug levels. (6) Upregulation/increased expression of FLT3 receptor and FL ligand can lead to increased signaling.