Format

Send to

Choose Destination
See comment in PubMed Commons below
Drug Resist Updat. 2009 Jun;12(3):81-9. doi: 10.1016/j.drup.2009.04.001. Epub 2009 May 20.

FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML.

Author information

  • 1Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Ellen_Weisberg@dfci.harvard.edu

Abstract

An appealing therapeutic target in AML is constitutively activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. There are currently several FLT3 inhibitors that are undergoing clinical investigation. However, the discovery of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to circumvent drug resistance. Here, we provide an overview of FLT3 inhibitors under preclinical and clinical investigation, and we discuss mechanisms whereby AML cells develop resistance to FLT3 inhibitors, and the ways in which combination therapy could potentially be utilized to override drug resistance. We discuss how the cross-talk between major downstream signaling pathways, such as PI3K/PTEN/Akt/mTOR, RAS/Raf/MEK/ERK, and Jak/STAT, can be exploited for therapeutic purposes by targeting key signaling molecules with selective inhibitors, such as mTOR inhibitors, HSP90 inhibitors, or farnesyltransferase inhibitors, and identifying those agents with the ability to positively combine with inhibitors of FLT3, such as PKC412 and sunitinib. With the widespread onset of drug resistance associated with tyrosine kinase inhibitors, due to mechanisms involving development of point mutations or gene amplification of target proteins, the use of a multi-targeted therapeutic approach is of potential clinical benefit.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk