ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside

Abstract

Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents.ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families. ABT-869 showed potent antiproliferative and apoptotic properties in vitro and in animal cancer xenograft models using tumor cell lines that were "addicted" to signaling of kinases targeted by ABT-869. When given together with chemotherapy or mTOR inhibitors, ABT-869 showed at least additive therapeutic effects. The phase I trial for ABT-869 was recently completed and it demonstrated respectable efficacy in solid tumors including lung and hepatocellular carcinoma with manageable side effects. Tumor cavitation and reduction of contrast enhancement after ABT-869 treatment supported the antiangiogenic activity. The correlative laboratory studies conducted with the trial also highlight potential biomarkers for future patient selection and treatment outcome.Parallel to the clinical development, in vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs. The future therapeutic roles of ABT-869 are currently been tested in phase II trials.

Figure 1

The chemical structure of ABT-869: N- [4-(3-amino-1H-indazol-4-yl)phenyl]- N1-(2-fluoro-5-methylphenyl) urea.

Figure 2

Kinase inhibition profile of ABT-869 against a broader range of kinases.

Figure 3

Inhibition of CSF1-primed LPS-induced TNF release. Mice were given ABT-869 (PO) at the indicated dose and 45 minutes later primed with CSF1 (1.8 μg IP). After 3.25 hours, LPS (300 μg IP) was administered. Serum TNF, expressed as mean ± SEM (n = 6), was assessed 1.5 hours later. CSF1 increased serum TNF induced by LPS by >4 fold (8 vs 37 ng/mL).

Figure 4

Efficacy of ABT-869 in representative xenografts. Efficacy was defined as percent of tumor size relative to vehicle-treated remaining after 3–4 weeks of dosing ABT-869 (10–25 mg/kg/day).

Figure 5

Efficacy of ABT-869 in combination with carboplatin-paclitaxel in a NSCLC xenograft. ABT-869 was administered orally at the indicated dose for 3 weeks and carboplatin-paclitaxel was administered weekly (IP and IV respectively) beginning 3 weeks after inoculation of H1299 cells into the flank of SCID/beige mice. Percent inhibition of tumor size relative to vehicle treated control was calculated at the end of the study is indicated in parentheses in the legend.

Figure 6

The FLT3-ITD signaling pathways. The presence of FLT3-ITD induces ligand-independent receptor dimerization and activates three major signaling pathways including PI3K/AKT, MAPK and STAT5 pathways. These signalings are transferred to nucleus, which lead to the transcription of genes involved in cell proliferation and survival.

Figure 7

Sequential real-time whole-body fluorescence imaging of HL60-RFP tumor growth in living mice. (A) Mice were treated with vehicle control. (B) Mice treated with ABT-869 (15 mg/kg/day). Arrow-pointed pictures show the direct view of distribution of blood vessel network on the tumor surface in the two representative mice. There is less of a tumor vessel network in ABT-869 treated mice. BF: bright field channel. RFP: RFP channel (The picture is modified from Leukemia Research 2008; 32:1091–1100 with permission) [32].

Figure 8

A model of enhanced STAT activation and overexpression of survivin leading to resistant phenotype in MV4–11-R cells. (Modified with permission from Blood journal) [50].

Figure 9

Computed tomography scan of tumor response and cavitation of lesions in a patient with metastatic lung carcinoma showing cavitation after 2 treatment periods. (with permission from Journal of Clinical Oncology) [64].