Pharmacogenetics

EGFR mutations in lung cancer: correlation with clinical response to Gefitnib therapy Paez, J. G. et al. Science 29 Apr 2004 [epub ahead of print]

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to Gefitinib Lynch, T. J. et al. N. Engl. J. Med. 350, 29 Apr 2004 [epub ahead of print]

Most patients with non-small cell lung cancer do not respond to the tyrosine kinase inhibitor gefitinib (Iressa; AstraZeneca), although those who do often have a dramatic clinical response. Two recent studies have identified similar point or deletion mutations in the epidermal growth factor receptor (EGFR) that could be predictive of which patients will benefit from gefitinib. Tumour biopsies from eight out of nine patients with gefitinib-responsive lung cancer carried these mutations, compared with none from seven non-responders. Paez et al. found EGFR mutations in 15 of 58 unselected tumours from Japan and 1 of 61 from the United States. Five out of five samples selected that had EGFR mutations were from treatment responders. The mutations are found in the ATP-binding pocket of the tyrosine kinase domain of EGFR and are associated with increased sensitivity to inhibition by gefitinib.

HIV-1

Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir Tuske, S. et al. Nature Struct. Mol. Biol. 11, 469–474 (2004)

HIV-1 viruses do not readily develop resistance to the prodrug tenofovir disoproxil fumarate (Viread; Gilead), which inhibits a viral protein reverse transcriptase (RT). A recent study compared structures of RT with bound tenofovir, and it helps explain the unusually low resistance of HIV to tenofovir. The structures show that mutations in RT that could reduce tenofovir incorporation would also substantially diminish the natural function of the enzyme. Furthermore, incorporated tenofovir can escape 'correction' activity of RT by adopting several conformations, thereby moving out of the active site of the enzyme with the growing chain.

Antisense

Determination of the role of the human Rnase H1 in the pharmacology of DNA-like antisense drugs Wu, H. et al. J. Biol. Chem. 279, 17181–17189 (2004)

Although it has been assumed that DNA-like antisense oligonucleotides (ASOs) cause target RNA reduction by binding to the target RNA and creating a DNA–RNA duplex that serves as a substrate for RNase H, definitive proof is lacking. By altering expression levels and cellular activity of RNase H1, the authors showed that RNase H1 is crucially involved in the effects of DNA-like ASOs. Furthermore, the data suggest that there might be other RNase H enzymes in mammalian cells that contribute to the activity of DNA-like ASOs.