SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer.

TLDR

SU11248 is an oral, multitargeted tyrosine kinase inhibitor that directly targets PDGFR, VEGFR, KIT, and FLT3, providing antitumor and anti‑angiogenic activity. The study aimed to evaluate SU11248’s activity against KIT in vitro and in vivo, to investigate KIT’s role in small cell lung cancer, and to assess SU11248’s potential clinical utility in SCLC. The authors examined KIT inhibition in vivo by treating mice bearing subcutaneous NCI‑H526 tumors with SU11248 or the unrelated KIT inhibitor STI571 (Gleevec), which also blocks Bcr‑Abl and PDGFRβ. SU11248 dose‑dependently inhibited stem‑cell‑factor‑stimulated KIT phosphorylation and proliferation in KIT‑positive NCI‑H526 cells, and in mice it produced greater tumor growth inhibition than STI571, correlated with stronger reductions in phospho‑KIT and phospho‑PDGFRβ, and when combined with cisplatin it yielded a significant tumor growth delay, supporting SU11248’s clinical potential in SCLC.

Abstract

The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta.