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

Sato, Takashi, Yang, Xiaochuan, Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441, White, Paul Charles ORCID: https://orcid.org/0000-0002-6562-4696, 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:	06 Jan 2024 03:57
URI:	https://orca.cardiff.ac.uk/id/eprint/28345

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