Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD–positive leukemic cells

Abstract

IntroductionAcute myeloid leukemia (AML) remains a difficult disease to treat. Patients typically respond to initial treatment with anthracycline and cytarabine-based induction chemotherapy, but most patients ultimately relapse and die of their disease. Internal tandem duplications (ITDs) of the juxtamembrane domain of the fetal liver tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in 20% to 30% of cases of de novo AML. FLT3 ITD mutations are the most common molecular abnormality associated with AML and presence of such a mutation predicts for a worse outcome for patients, 1-3 particularly those with a high mutant-to-normal FLT3 allelic ratio. 4 An additional 5% to 7% of AML patients have an activating mutation of the FLT3 kinase activation loop. 5 There is substantial experimental and clinical evidence to support the hypothesis that FLT3 mutations are important in the initiation or maintenance of AML in some patients. Activating mutations of FLT3 result in constitutive activation of FLT3 tyrosine kinase activity and can transform factor-dependent hematopoietic cells as evidenced by conversion to factor-independent growth and formation of tumors in immunodeficient mice. [6][7][8] In addition, retroviral transduction of primary murine bone marrow with an AML patient-derived FLT3 ITD cDNA results in a lethal myeloproliferative syndrome. 9 Finally, retroviral transduction of bone marrow derived from promyelocytic leukemia/retinoic acid receptor ␣ (PML-RAR␣) transgenic mice with FLT3 ITD results in a marked increase in the incidence of acute progranulocytic (APL)-like leukemia in such mice when compared with mice that received a transplant of mock-transduced bone marrow. 10 These findings suggest that FLT3 may be a target for molecular therapy, analogous to that of BCR-ABL in chronic myeloid leukemia (CML). In CML, the use of single-agent imatinib (STI571, Gleevec) is associated with impressive response rates and is now considered the standard frontline nontransplantation medical therapy. 11,12 Agents capable of inhibiting FLT3 kinase have been developed and display promising preclinical activity. [13][14][15][16][17][18][19] These agents are capable of halting leukemic cell proliferation and inducing apoptosis in vitro and in different animal models. Several of these FLT3 inhibitors are currently being studied in phase-1 and -2 clinical trials of patients with AML but thus far have demonstrated only modest single-agent activity. [20][21][22] These results are somewhat analogous to those seen using imatinib to treat patients with CML blast crisis, where the rate of complete hematologic or cytogenetic response, as well as the duration of such responses, were markedly inferior to the results obtained in treating chronicphase patients. This experience suggests that FLT3 inhibitors may need to be combined with other antileukemic treatments to obtain the best clinical results. Theoretically, it would be advantageous to add chemotherapy agents that act synergistically with FLT3 We sought to profile the activit...

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

“…Because of the ability to cause G 2 arrest, PKC412 is synergistic with drugs that are active in the G 2 /M phase, such as colchicine, in these cell lines. This may be an important advantage for the usage of PKC412 over other FLT3 inhibitors, because such effects have not been demonstrated with other FLT3 inhibitors (Levis et al, 2004;Yee et al, 2004). For the same reason, PKC412 may be antagonistic with drugs that synchronize target cells in late G 1 to early S phase, such as aphidicolin, in FLT3 mutation-negative leukemias.…”

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

“…They found that simultaneous exposure and sequential exposure with CEP-701 added after chemotherapeutic agents produced synergistic effects, whereas the reverse-sequence exposure resulted in an antagonistic effect. Yee et al 39 reported that SU11248 had synergistic effects with daunorubicin and cytarabine in several leukemic cell lines carrying FLT3 mutations. A similar tendency was observed in our study, although the FLT3 inhibitors used were different in each study.…”

Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway

“…SU11248, another FLT3 inhibitor, also was found to synergistically interact with Ara-C or Dox in vitro when given concurrently. 23 In contrast, pretreatment with ABT-869 followed by chemotherapy yielded an undesirable antagonistic effect. The antagonism observed could result from G 1 -phase cell cycle arrest and the removal of cells in the S-G 2 /M boundary by ABT-869, resulting in more cells under quiescent condition.…”

“…It has been reported that combination of SU11248 with Ara-C or Dox exerted synergistic effects 23 and CEP-701 showed in vitro sequence-dependent synergistic cytotoxic effects on FLT3-ITD leukemia cells when combined with chemotherapy. 24 In this study, the sequence-dependent synergism was attributed to CEP-701-induced cell cycle arrest, and it was speculated that the sequential treatment first induced pro-apoptotic signals, then withdrew pro-survival signals.…”