Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family

Abstract

Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-a, and PDGFR-b. Cediranib inhibited VEGF-A-stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC 50 ¼ 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC 50 ¼ 1-3 nmol/L) and in a stem cell factor-induced proliferation assay (IC 50 ¼ 13 nmol/L). Furthermore, phosphorylation of wildtype c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (!1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-b and PDGFR-a was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC 50 ¼ 12-32 nmol/L) and PDGF-BB-stimulated cellular proliferation (IC 50 ¼ 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-b phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-a and PDGFR-b was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-a and PDGFR-b. Mol Cancer Ther; 10(5); 861-73. Ó2011 AACR.

Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors or Soft-Tissue Sarcoma

“…10). However, similar to imatinib, cediranib was not active against the T670I KIT gatekeeper mutation (ATP-binding region of KIT) or the D816V/D816Y KIT mutations (10). We do know that VEGFR was inhibited by cediranib, as shown by the common side effect of hypertension and the impact on circulating VEGF and sVEGFR-2.…”

“…Cediranib is an oral, highly potent, VEGF signaling inhibitor with activity against all three VEGFRs and additional activity versus KIT (8)(9)(10). In vitro, cediranib has been shown to inhibit two mutant forms of KIT (V654A, N822K) associated with secondary resistance to imatinib, but has not been shown to inhibit all mutants thought to be responsible for the development of resistance to imatinib and sunitinib (10).…”

“…In vitro, cediranib has been shown to inhibit two mutant forms of KIT (V654A, N822K) associated with secondary resistance to imatinib, but has not been shown to inhibit all mutants thought to be responsible for the development of resistance to imatinib and sunitinib (10). In phase I and II studies, cediranib has demonstrated evidence of antitumor activity in patients with advanced solid tumors, both as a single agent and in combination with other anticancer strategies (11)(12)(13)(14)(15)(16)(17).…”

Hypertension in cancer patients treated with anti-angiogenic based regimens

“…Cediranib (Recentin®, AZD2171, Astra-Zeneca), a relatively new agent, targets VEGFR 1, 2, and 3, and c-KIT [74][75][76].…”

PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary

“…We therefore decided to investigate this mechanism of toxicity by co-dosing rats with AZ12585313 and AZD2171 (cediranib), which are specific inhibitors of the PDGFR and VEGFR receptors, respectively (Brave et al 2011). Two HW rats were treated with AZ12585313 at 25 mg/kg BID and AZD2171 at 2.5 mg/kg QD for 9 days.…”