SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer.
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.
Preclinical Research and Exploratory Development, SUGEN, Inc., South San Francisco, California 94080, USA. tinya-abrams@sugen.com
Tinya J
TJ
Abrams
Leslie B
LB
Lee
Lesley J
LJ
Murray
Nancy K
NK
Pryer
Julie M
JM
Cherrington
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019089:Stem Cell Factor / Q000502:physiology; D000077210:Sunitinib; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D019089:Stem Cell Factor; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D000077210:Sunitinib