Integrin-linked kinase inhibitor KP-392 demonstrates clinical benefits in an orthotopic human non-small cell lung cancer model.
BACKGROUND
The overexpression of integrin-linked kinase (ILK) has been implicated in the promotion of tumor invasion and metastasis. We studied the anticancer effects of KP-392, a potent selective inhibitor of ILK in the NCI-H460 cell line. In vitro, KP-392 inhibited ILK activity of H460 cells. In vivo, the effect of KP-392 was investigated in a metastatic H460 orthotopic lung cancer model.


METHODS
Intraperitoneal KP-392 (5 mg/day per animal) was administered both alone and in combination with cisplatin (5 mg/kg per week for 3 weeks). In group I, all treated animals were followed until death to assess therapeutic effect on survival. In group II, tumor growth and metastasis were evaluated by sacrificing one animal from each treatment when a control animal died.


RESULTS
Both cisplatin and KP-392 significantly enhanced survival (37.8 +/- 3.7 and 34.9 +/- 5.2 days) compared with the control (30.2 +/- 3.6 days, p < 0.0001 and p = 0.0418, respectively), and the survival benefit from combination treatment was greater than that of either agent alone (45.8 +/- 3.9 days, p < 0.0001). Although KP-392 alone did not impact the incidence of metastasis, in combination with cisplatin a consistent trend of inhibition was seen for metastases in the kidney, bone, and the contralateral lung. KP-392 was well tolerated throughout the study. KP-392 demonstrated increased tumor necrosis and decreased nuclear phospho-protein kinase/Akt but did not change the levels of phospho-extracellular signal-regulated kinase 1/2.


CONCLUSIONS
ILK inhibitor does not enhance the toxicity of standard chemotherapy and may have a beneficial therapeutic effect in lung cancer.
Liu
Jiang
J
Division of Thoracic Surgery, Toronto General Hospital, University Health Network and the Department of Surgery and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Costello
Penny C
PC
Pham
Nhu-An
NA
Pintillie
Melania
M
Jabali
Mogjan
M
Sanghera
Jasbinder
J
Tsao
Ming-Sound
MS
Johnston
Michael R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D000099200:Scaffold Protein ILK
D000970:Antineoplastic Agents; D002945:Cisplatin; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK