PI3K INHIBITION COMBINED WITH STANDARD CHEMOTHERAPY EFFECTIVELY INHIBITS KIT MUTANT AML
Author(s): ,
Montserrat Estruch
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark
,
Kristian Reckzeh
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health and Medical Sciences,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark
,
Anders Centio
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark
,
Camilla Vittori
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark
,
Kristine Gustavsen
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark
Kim Theilgaard-Mönch
Affiliations:
Finsen Laboratory,Rigshospitalet/National Univ. Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen,Denmark;Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health and Medical Sciences,Copenhagen,Denmark;Department of Hematology,Rigshospitalet,Copenhagen,Denmark;Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences
EHA Library. Estruch M. Jun 15, 2019; 267280; PS979
Montserrat Estruch
Montserrat Estruch
Contributions
Abstract

Abstract: PS979

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

AML patients currently demonstrate a dismal overall survival rate (5y OS 25%) in response to standard chemotherapy regimens. The c-KIT-encoded receptor protein tyrosine kinase for stem cell factor (KIT) is recurrently mutated in AML (5%). KIT mutations frequently cooccur in AML patients with inv(16)/t(16/16) (15%) and t(8;21) (38%) driver aberrations where they confer inferior prognosis. KIT activation, promoted by the stem cell factor, is essential for survival, migration, and proliferation of normal hematopoietic stem and progenitor cells (HSPCs). KIT mutations in AML, like the KIT(D816Y) in exon 17, confer conformational changes leading to constitutive activation of PI3K and its downstream signalling pathways, which ultimately promotes cell growth, survival and chemotherapy resistance. 

Aims

In the present we applied the inv(16)/KIT(D816Y) mouse AML model to investigate whether therapeutic targeting of PI3K in combination with standard chemotherapy would inhibit growth and survival of AML synergistically.

Methods

Gene Expression Profiling of sorted normal BM progenitor cells and inv(16)/KIT(D816Y) AML cells as well as Western blot analyses demonstrated high PI3K pathway activity in AML cells (i.e. PI3K-beta and PI3K-delta) implicating that the inv(16)/KIT(D816Y) AML model would allow to explore the therapeutic potential of PI3K inhibition alone and in combination with standard chemotherapy in a preclinical AML trial program.

Results

Colony forming-cell (CFC) assays were applied to assess the inhibitory effect of a range of PI3K inhibitors and standard chemotherapeutics on clonogenic growth of inv(16)/KIT(D816Y) AML cells vs wild-type BM cells. Among all tested drugs the pan-PI3K inhibitor BKM120 (IC50 360nM), Doxorubicin (IC50 5nM) and Ara-C (Cytarabine) (IC50 28nM) were selected and subjected to subsequent drug combination tests, which demonstrated high synergy scores for BKM120+Doxorubicin (Delta Score=21) and for BKM120+Ara-C (Delta Score=6).

We subsequently conducted in vivo pre-clinical AML trials using varying doses of BKM120 alone and in combination with varying doses of a Doxorubicin/Ara-C 3+5 chemotherapy regimen. Treatment with BKM120 per oral gavage demonstrated in vivo inhibition of the PI3K pathway, decreased AML burden in bone marrow (BM), spleen, and peripheral blood (PB), and reduced splenomegaly in a dose dependent manner (BKM120: 50mg/kg/d and 30mg/kg/d). As expected, the Doxorubicin/Ara-C 3+5 chemotherapy regimen also inhibited in vivo AML growth in a dose dependent manner (DA-1:  0,75 mg/kg/d1-3 + 25mg/kg/d1-5, DA-2: 1,5mg/kg/d1-3 + 50mg/kg/d1-5).  

Combinatorial treatment with BKM120 and Doxorubin/Ara-C, increased survival of mice with inv(16)/KIT(D816Y) AML significantly (i.e. 30-42d) compared to untreated mice (17-18d, p>0,001) and mice subjected to single treatment with either BKM120 (22-28d, p=0,004) or chemotherapy (21-22d, p>0,001).

Conclusion
The present study implicates that targeted inhibition of the KIT/PI3K signaling axis enhances the therapeutic efficiency of standard chemotherapy in KIT mutant AML. Significantly, our findings provide a rationale for development of precision medicine strategies that target cancer-specific vulnerabilities such as oncogenic signaling in individual AML patients in order to enhance their sensitivity toward conventional chemotherapy, leading to improved clinical outcome.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): AML, Chemotherapy, PI3K

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