FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

Sato, Takashi, Yang, Xiaochuan, Knapper, Steven, White, Paul Charles, Smith, B. Douglas, Galkin, Steven, Small, Donald, Burnett, Alan Kenneth and Levis, Mark 2011. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 117 (12) , pp. 3286-3293. 10.1182/blood-2010-01-266742

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Abstract

We examined in vivo FLT3 inhibition in AML patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly-diagnosed AML patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly-diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. Following intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly-diagnosed patients, while they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level following chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors, and furthermore suggest a rationale for targeting FL as a therapeutic strategy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Society of Hematology
ISSN:	0006-4971
Last Modified:	08 Aug 2019 20:38
URI:	http://orca-mwe.cf.ac.uk/id/eprint/28345

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