Gene Signatures Predicting Sensitivity to ABT-263
ABT-263 is a Bcl-2 family member inhibitor with single-agent activity in numerous small cell lung carcinoma (SCLC) and leukemia/lymphoma cell lines in vitro and in vivo and is currently in ongoing clinical trials. Tahir and colleagues show that higher Mcl-1 expression was associated with resistance, and higher Bcl-2 and Noxa expression was associated with sensitivity to ABT-263 in both SCLC and leukemia/lymphoma cells lines. They also identified gene expression signature sets that are predictive of response to ABT-263. These markers and signatures are beneficial for the clinical development of ABT-263, providing guidance in the selection of patients in future clinical trials.
AKT1 and EGFR Polymorphisms in Lung Cancer
EGFR and K-Ras mutations are associated with sensitivity/resistance to EGFR tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC), but do not explain all clinical outcomes. Similarly, the large interindividual variability in toxicity makes identification of novel pharmacogenetic markers attractive. This is the first study to show that the AKT1-SNP- A/A genotype is associated with shorter overall survival in NSCLC patients treated with gefitinib. Furthermore, the EGFR-191C/A, 216G/T, and R497K polymorphisms were associated with gastrointestinal toxicity. These polymorphisms can be assessed with a simple blood test and might enhance the selection of patients for EGFR-TKI treatment by identifying a genetically high-risk subgroup for drug-resistance or toxicity.
Drug Cytotoxic Effects on SP and Non-SP Cells
Prostate cancer stem/progenitor cells can provide critical functions for tumor growth, metastases, resistance to current therapies, and disease relapse. Mimeault and colleagues describe the inhibition of hedgehog and EGFR signaling cascades, using gefitinib and cyclopamine, which improves the cytotoxic effects induced by the current clinical chemotherapeutic drug, docetaxel, on CD133+/CD44high/AR−/low side population (SP) cells with stem cell-like properties and the CD133−/CD44low/AR+ non-SP cell fraction from PC cells. These findings suggest that co-targeting of hedgehog and EGFR might constitute a novel therapeutic strategy for improving the efficacy of docetaxel-based therapies and, thereby, eradicate the total PC cell mass and prevent disease relapse.
Pharmacology and Antitumor Activity of PHT-427
Akt and phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1) are components of the PI-3-kinase cell survival signal pathway. PDPK1 phosphorylates and activates AKT but also signals independently. The study reports the in vivo antitumor activity of PHT-427, a computationally designed small molecule that binds to the PI-3-phosphate binding pleckstrin homology (PH) domain of Akt and PDPK1, inhibiting their activity in cells and in animal tumors. The greatest antitumor activity is observed in tumors with activated PI-3-kinase signaling and less activity in tumors with mutant K-RAS. PHT-427 is an orally active antitumor agent and exhibits low toxicity.
- ©2010 American Association for Cancer Research.