Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature

Sigal Tavor, Tali Shalit, Noa Chapal Ilani, Yoni Moskovitz, Nir Livnat, Yoram Groner, Haim Barr, Mark D. Minden, Alexander Plotnikov, Michael W. Deininger, Nathali Kaushansky, Liran I. Shlush

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Novel targeted therapies improve the survival of specific subgroups (defined by genetic variants) of patients with acute myeloid leukemia (AML), validating the paradigm of molecularly targeted therapy. However, identifying correlations between AML molecular attributes and effective therapies is challenging. Recent advances in high-throughput, in vitro drug sensitivity screening applied to primary AML blasts were used to uncover such correlations; however, these methods cannot predict the response of leukemic stem cells. Our study aimed to predict in vitro response to targeted therapies, based on molecular markers, with subsequent validation in leukemic stem cells. We performed ex vivo screening of sensitivity to 46 drugs on 29 primary AML samples at diagnosis or relapse. Using unsupervised hierarchical clustering analysis we identified a group with sensitivity to several tyrosine kinase inhibitors, including the multi-tyrosine kinase inhibitor, dasatinib, and searched for correlations between the response to dasatinib, exome sequencing and gene expression in our dataset and in the Beat AML dataset. Unsupervised hierarchical clustering analysis of gene expression resulted in clustering of dasatinib responders and non-responders. In vitro response to dasatinib could be predicted based on gene expression (area under the curve=0.78). Furthermore, mutations in FLT3/ITD and PTPN11 were enriched in the dasatinib-sensitive samples as opposed to mutations in TP53 which were enriched in resistant samples. Based on these results, we selected FLT3/ITD AML samples and injected them into NSG-SGM3 mice. Our results demonstrate that in a subgroup of FLT3/ITD AML (4 out of 9) dasatinib significantly inhibited leukemic stem cell engraftment. In summary we show that dasatinib has an anti-leukemic effect both on bulk blasts and, more importantly, on leukemic stem cells from a subset of AML patients that can be identified based on mutational and expression profiles. Our data provide a rational basis for clinical trials of dasatinib in a molecularly selected subset of AML patients.

Original languageEnglish
Pages (from-to)2795-2804
Number of pages10
JournalHaematologica
Volume105
Issue number12
DOIs
StatePublished - 1 Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Ferrata Storti Foundation

Funding

This research was supported by a grant from the Nancy and Stephen Grand Israel National Center for Personalized Medicine to HB and by the EU horizon 2020 grant project MAMLE ID: 714731, LLS grant ID: RTF6005-19, and IMOS-712843 awarded to LIS. LIS is an incumbent of the Ruth and Louis Leland career development chair. NK is an incumbent of the Applebaum Foundation Research Fellow Chair. This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Rising Tide Foundation and the Applebaum Foundation.

FundersFunder number
Applebaum Foundation
Leukemia and Other Blood Disorders
Nancy and Stephen Grand Israel National Center for Personalized Medicine
Sagol Institute for Longevity Research
Horizon 2020 Framework Programme
Horizon 2020RTF6005-19, 714731, IMOS-712843
Rising Tide Foundation

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