Activation of FGFR1β signaling pathway promotes survival, migration and resistance to chemotherapy in acute myeloid leukemia cells

Abstract

Fibroblast growth factors (FGFs) are important regulators of hematopoiesis and have been implicated in the tumorigenesis of solid tumors. Recent evidence suggests that FGF signaling through FGF receptors (FGFRs) may play a role in the proliferation of subsets of acute myeloid leukemias (AMLs). However, the precise mechanism and specific FGF receptors that support leukemic cell growth are not known. We show that FGF-2, through activation of FGFR1b signaling, promotes survival, proliferation and migration of AML cells. Stimulation of FGFR1b results in phosphoinositide 3-kinase (PI3-K)/Akt activation and inhibits chemotherapy-induced apoptosis of leukemic cells. Neutralizing FGFR1-specific antibody abrogates the physiologic and chemoprotective effects of FGF-2/FGFR1b signaling and inhibits tumor growth in mice xenotransplanted with human AML. These data suggest that activation of FGF-2/ FGFR1b supports progression and chemoresistance in subsets of AML. Therefore, FGFR1 targeting may be of therapeutic benefit in subsets of AML. Leukemia (2006) 20, 979-986.

Isolation and characterization of erlotinib-resistant human non-small cell lung cancer A549 cells

“…Through the activation of FGFR1β signaling, FGF2 promotes the survival and proliferation of tumors. Stimulation of FGFR1β results in PI3K/ Akt activation and causes resistance to anti-cancer agents (14,15). Neutralizing FGFR1-specific antibody abrogates the physiologic and chemoprotective effects of FGF2/FGFR1β signaling (15).…”

The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion

“…48,49 Moreover, it should be emphasized that the HL60AR cell subclone we employed for this study is drug resistant. 17 Interestingly, a recent report has highlighted that IGF-I expression levels are higher in AML patients in the refractory stage, after ARA-C combined chemotherapy, than those in patients at diagnosis.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…Many different types of drug-resistant leukemias have been examined by genomic approaches to identify genes involved in drug resistance. 71,[126][127][128][129][130][131][132] Some of the genes implicated in the drug resistance include genes involved in: apoptosis caspase 9 (CASP9), signaling (HA-RAS), tumor necrosis factor receptorassociated protein-1 (TRAP1), fibroblast growth factor receptor-1 (FGF-R1), IGF-1, Rab protein-11 (RAB-11), phosphoprotein c-abl-regulated kinase-ligand (P-Crk-L), sphingosine kinase-1 (SPHK1), Burton's tyrosine kinase (BTK) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22). Genes implicated in drug resistance are also those involved in drug metabolism such as cyclooxygenase-1 (COX-1) and drug transporters including ATP-binding cassette (ABC) subfamily b, (MDR/ TAP), member 1 (ABCB1), ABC subfamily b, member 2 (ABCG2) and multidrug-resistant protein 1 (MRP1).…”