Small Cell Lung Cancer: Screening of Kinase Inhibitors.

Small cell lung cancer (SCLC) exhibits extreme numbers of circulating tumor cells (CTCs) that are operative in tumor dissemination and possibly drug resistance, ultimately resulting in a dismal prognosis. Tumor cells depend on kinases, which are triggered by a range of growth factors for their malignant proliferation. Insulin-like growth factor-I receptor (IGF-1) and vascular endothelial growth factor receptor (VEGFR), c-Kit, epidermal growth factor receptor (EGFR), as well as downstream signaling transmitters such as phosphoinositide 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) and a range of other kinases were investigated as potential anti-tumor targets in SCLC. Despite the expression of rational targets, the studies with tyrosine kinase inhibitors (TKIs) in SCLC have been very disappointing in the clinic. The preclinical activity of kinase inhibitors against native and resistant SCLC cell lines failed to predict efficacy in patients. Screening of a kinase inhibitor library showed activity of most compounds against single SCLC CTC cells but high chemoresistance of BHGc10 spheroids (termed tumorospheres). Only a few hydrophobic multitarget inhibitors proved active against the spheroids, and drugs that failed in clinical trials targeting IGF-1R, AURORA kinase and Polo kinases showed low activity against CTC tumorospheres. These results demonstrate that for SCLC, kinase inhibitors should be tested against spheroids to obtain a better prediction of their potential clinical activity.