Integrin-Linked Kinase Inhibitor KP-392 Demonstrates Clinical Benefitsin an Orthotopic Human Non-small Cell Lung Cancer Model

IntroductionThe 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.MethodsIntraperitoneal 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.ResultsBoth 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.ConclusionsILK inhibitor does not enhance the toxicity of standard chemotherapy and may have a beneficial therapeutic effect in lung cancer.