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The stromal microenvironment provides an escape route from FLT3 inhibitors through the GAS6-AXL-STAT5 axis
Anna Orlova1, Heidi A. Neubauer1 and Richard Moriggl1,2
1Institute of Animal Breeding and Genetics, University of Veterinary Medicine and 2Medical University Vienna, Vienna, Austria E-mail: RICHARD MORIGGL - richard.moriggl@vetmeduni.ac.at
doi:10.3324/haematol.2019.225862
The FLT3-ITD mutation is one of the most common rearrangements in acute myeloid leukemia (AML), and is particularly associated with poor prognosis and recur- rent development of resistance. In 2017, the FLT3 tyrosine kinase inhibitor (TKI) midostaurin was approved for use in combination with standard cytarabine-based chemotherapy. Several other small molecule inhibitors against FLT3 tyrosine kinase are currently being tested in phase III clinical trials (e.g. gilteritinib and quizartinib). Despite successful application of the targeted therapy in patients, emergence of resistance is still a major drawback in clinical practice.1 A better understanding of resistance mechanisms in cancer is key to defining better treatment strategies for patients. The new study by Dumas et al. in this issue of the Journal unravels mechanisms involving the tyrosine kinase receptor AXL contributing to the develop- ment of resistance to quizartinib in FLT3-ITD+ AML.2
AXL belongs to the family of TAM receptors, and together with two other members, TYRO3 and MER, it was first shown to have malignant roles in solid cancers.3,4 AXL was identified as one of the most prominently activated tyrosine kinase receptors in colorectal, esophageal, thyroid, breast, prostate and lung carcinomas, and its activation was associated with transforming growth factor beta (TGFβ) signaling.4,5 AXL is selectively activated by GAS6 ligand, which has a signifi- cantly higher affinity to AXL compared to the other family members. Further ligands for TAM receptors include Protein S, Tubby, Tubby-like protein 1, and Galectin-3.4 Soluble forms of AXL (sAXL) are also reported, and result from cleavage by ADAM10/17 proteases in the plasma of patients with advanced liver cancer; they are, therefore, of extremely impor- tant diagnostic value for liver cancer progression.6 TAM recep- tors are involved in processes promoting cell growth and sur- vival, cell adhesion, migration, blood coagulation, and cytokine release.7 However, TAM receptors were also reported to impede cancer cells through stimulation of tumor cell-target- ing immune cells.8
The new findings reported by Dumas et al.2 confirm an important cancer-protective role for the stromal microenviron- ment, mechanistically identifying that it induces cytokine pro- duction and hypoxic conditions to trigger the activation of AXL and the transcription factor STAT5 in FLT3-ITD+ AML (Figure 1A). The authors further show that stroma-induced expression of AXL, mediated by STAT5, drives progression of the disease. The paper provides evidence that growth arrest specific protein 6 (GAS6) ligand secreted from stromal cells activates AXL and, together with hypoxia, contributes to AML progression and resistance to quizartinib. Notably, a bypass mechanism was described involving activation of the AXL receptor kinase to compensate for FLT3 inhibition to promote AML progression.
Interestingly, similar findings also implicated AXL activation, together with another receptor tyrosine kinase MET, in driving resistance mechanisms in HER2-positive gastric cancer with
TKI treatment.9 Here, the authors generated and exploited afa- tinib-resistant gastric cancer cell lines to identify AXL and MET as key players in the development of drug resistance. Yoshioka et al. proposed combinatorial treatment using afatinib with pan-kinase inhibitor cabozantinib, which also targets AXL/MET, to prevent development of therapy resistance or to potentially sensitize patients who have already developed resistance.9
STAT5A/B proteins are key downstream transcription fac- tors in FLT3-ITD+ AML, and they mediate signals from hyper- active FLT3. STAT5 inhibition was reported to be a promising strategy for FLT3-ITD+ AML treatment.10-13 The oncogenic roles of highly tyrosine-phosphorylated STAT5 (pYSTAT5) in hematopoietic diseases were best exemplified using graded expression and activity levels of STAT5A/B in gain-of-function transgenic mouse models.14,15 Important downstream transcrip- tional changes triggered by STAT5 in neoplastic myeloid cells can involve enhanced expression of DNMT3A, BCL2 or D-type cyclin family members, as well as MYC induction. This panel of downstream STAT5 target genes has now been expanded to include AXL in quizartinib-resistant FLT3-ITD+ AML, and it will be of particular interest to explore whether this finding is also applicable in other cancers.2 Interestingly, TET or DNMT3 genes are often mutated in AML, and both have been reported to either form protein interactions with STAT5 or undergo direct gene regulation by STAT5. In particular, mutations in chromatin modifiers TET2, DNMT3A, ASXL1, IDH1/2, as well as STAT5, were found to be of important prognostic value in FLT3-ITD+ mutated AML cases. It will be important to explore further the impact of these proteins and the chromatin land- scape on the GAS6-AXL-STAT5 AML progression axis.16,17
A previous study also examined the effects of PI3K/AKT/mTOR inhibitors on a FLT3-ITD+ AML cell line compared with a cell line harboring point mutations within the TKD2 domain of FLT3 (FLT3-TKD). The authors reported that FLT3-ITD+ cells are more resistant to the aforementioned FLT3 inhibitors compared with FLT3-TKD+ cells. The authors pro- posed hyperactivation of STAT5 in FLT3-ITD+ AML cells as a protective mechanism against PI3K/AKT/mTOR inhibition.18 Interestingly, Dumas et al. showed in their model that inhibi- tion of PI3K/AKT signaling had no effect on AXL or STAT5 phosphorylation, and, therefore, this did not directly mediate the development of resistance to therapy.2
Based on these recent findings, we used public gene expres- sion datasets available from the Oncomine database to inde- pendently evaluate AXL gene expression data from patients with AML as well as from patients with other hematopoietic cancers.19 As also discussed by Dumas et al., we found AXL to be significantly up-regulated in AML patient samples (Figure 1B). Interestingly, upregulation of AXL was also clearly evident in various subtypes of B-cell and T-cell leukemias/lymphomas (Figure 1B), suggesting a potentially broader relevance for the oncogenic action of AXL upregulation in hematopoietic can-
haematologica | 2019; 104(10)
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