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Akt and p38 MAPK synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells

Weisberg, Ellen and Liu, Qingsong and Zhang, Xin and Nelson, Eric and Sattler, Martin and Liu, Feiyang and Nicolais, Maria and Zhang, Jianming and Mitsiades, Constantine and Smith, Robert and Stone, Richard and Galinsky, Ilene and Nonami, Atsushi and Griffin, D. James and Gray, Nathanael and Carmeli, Yael (2013) Akt and p38 MAPK synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells. PLoS One. , 8 (2). e56473. .

Abstract

Tyrosine kinase inhibitor (TKI)-treated acute myeloid leukemia (AML) patients commonly show rapid and significant peripheral blood blast cell reduction, however a marginal decrease in bone marrow blasts. This suggests a protective environment and highlights the need for a greater understanding of stromal:leukemia cell communication. To address this, we used a novel adherent stroma-based co-culture system as the foundation for a chemical screen designed to identify novel kinase inhibitors capable of potentiating the apoptosis-inducing effects of TKIs against adherent stroma-protected mutant FLT3-positive cells. Screenings led to the identification of selective inhibitors of Akt and MAPK, mediators of signaling pathways implicated in TKI exposure-induced drug resistance, and found to be activated in stromal cells in direct contact with leukemia. Although constitutive MAPK and Akt activation is characteristic of mutant FLT3-transformed cells, our screen suggests that Akt and MAPK may play an unexpected role in stromal protection of TKI-treated cells. In addition, it is common to observe residual Akt and MAPK activity following FLT3 inhibitor treatment. Our findings highlight the potential importance of these signaling factors in leukemia survival and stromal protection of TKI-treated leukemia, and support the use of the co-culture chemical screen to identify agents able to potentiate TKI anti-leukemia activity.

Key words: acute myeloid leukemia, FLT3 inhibitor, multi-targeted kinase inhibitor, PKC412, AC220, Akt, p38 MAPK, stromal-mediated chemoresistance, synergy

Item Type: Article
Date Deposited: 08 May 2016 23:45
Last Modified: 08 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/8102

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