Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

Abstract

Synopsis The presence of FLT3 mutations in AML carries a particularly poor prognosis making the development of FLT3 inhibitors an imperative goal for these patients. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the imminent approval by the FDA of FLT3 inhibitors for the treatment of AML. Unfortunately, the initial success stories have been rapidly followed by the emergence of clinical resistance. While novel FLT3 inhibitors are actively being developed, studies into mechanisms of resistance to these drugs raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease in this AML.

<p>Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date</p>

“…1 FL binds to the FLT3 receptor and in turn leads to restoration of FLT3 and downstream MAPK signaling, allowing FLT3-ITD AML cells to survive. 59 The addition of exogenous FL to leukemia cell lines in vitro protects cells and increases the IC 50 for FLT3 inhibition by activating the MAPK pathway. 56 In agreement with this model, FL expression also increases in patients treated with FLT3 inhibitors.…”

Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: the Path to Least Resistance

“…Chemotherapy plays a significant role in disease progression in AML, instigating new mutations in founding clones or one of their subclones, which then can undergo selection and clonal expansion [7]. Chemotherapies can also select for resistant clones or LSCs (discussed above) which are present at diagnosis at very low frequencies [151]. Patients with FLT3-ITD mutation often form resistance to TKIs following the acquisition of point mutations in the activation loop of the tyrosine kinase domain 1 (i.e.…”

Molecular Interaction Between the Microenvironment and FLT3/ITD+ AML Cells Leading to the Refractory Phenotype

“…Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD), which are expressed in human acute myeloid leukemia (AML) stem cells, are found in ~30% of patients with AML [3]. FLT3/ITD + AML is one of the most intractable hematological malignancies because of the emergence of resistant clones to FLT3/ITD inhibitors or chemotherapies [3,4]. FLT3/ITD allows ligand-independent activation and phosphorylation of the FLT3 receptor.…”

“…For instance, AC220 (quizartinib), a second-generation class III tyrosine kinase inhibitor (TKI) used in phase II clinical trials, is a very potent and specific inhibitor of FLT3/ITD compared with other TKIs; however, FLT3/ITD + cells can become refractory to AC220 [9,27]. The mechanism responsible for the resistance of FLT3/ITD + AML cells against FLT3/ITD inhibitors can be classified into FLT3/ITD-dependent and FLT3/ITDindependent mechanisms [4,28]. The former is generally acknowledged as the acquisition of mutations in the FLT3 gene in addition to preexisting FLT3/ITD mutations.…”

“…The emergence of additional mutations in the kinase domain makes FLT3/ITD no longer sensitive to FLT3/ITD inhibitors by altering the three-dimensional structure of FLT3 kinase, making FLT3 inhibitors difficult to physically interact with FLT3 protein. This mechanism is detailed in the excellent reviews [4,28]. Although the development of further mutations in the FLT3 gene is associated with being refractory to the FLT3 inhibitor, most patients who became refractory to the FLT 3/ITD inhibitors lacked additional mutation in the FLT3 gene.…”