Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients
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Mara W. Rosenberg1,2, Kevin Watanabe-Smith1,2, Jeffrey W. Tyner1,4, Cristina E. Tognon1,2,3, Brian J. Druker1,2,3 and Uma Borate2
1 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
2 Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA
3 Howard Hughes Medical Institute, Portland, OR, USA
4 Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
|Mara W. Rosenberg,||email:||[email protected]|
Keywords: acute myeloid leukemia; drug sensitivity; midostaurin; drug resistance; FLT3
Abbreviations: AML: acute myeloid leukemia; FLT3-ITD: FLT3-internal tandem duplication; TKI: tyrosine kinase inhibitors; ELN Guidelines: European Leukemia Network Guidelines
Received: April 23, 2020 Accepted: June 05, 2020 Published: July 21, 2020
Acute myeloid leukemia (AML) is a heterogeneous malignancy with the most common genomic alterations in NPM1, DNMT3A, and FLT3. Midostaurin was the first FLT3 inhibitor FDA approved for AML and is standard of care for FLT3 mutant patients undergoing induction chemotherapy [
We performed an ex vivo drug sensitivity screen on primary and relapsed AML samples with corresponding targeted sequencing and RNA sequencing. We observed a correlation between FLT3-ITD mutations and midostaurin sensitivity as expected and observed KRAS and TP53 mutations correlating with midostaurin resistance in FLT3-ITD negative samples. Further, we identified genes differentially expressed in sensitive vs. resistant samples independent of FLT3-ITD status. Within FLT3-ITD mutant samples, over-expression of RGL4, oncogene and regulator of the Ras-Raf-MEK-ERK cascade, distinguished resistant from sensitive samples. Overall, this study highlights the complexity underlying midostaurin response. And, our results suggest that therapies that target both FLT3 and MAPK/ERK signaling may help circumvent some cases of resistance.
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