Pharmacogenetics: EGFR mutations in lung cancer are linked to response to gefitinib therapy. Studies show that patients with non-small cell lung cancer who respond to gefitinib often have mutations in the epidermal growth factor receptor (EGFR). These mutations are found in the ATP-binding pocket of the tyrosine kinase domain of EGFR and are associated with increased sensitivity to gefitinib. Eight out of nine patients with gefitinib-responsive lung cancer had these mutations, while none of the seven nonresponders did. 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. HIV-1: Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir 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: The role of the human Rnase H1 in the pharmacology of DNA-like antisense drugs is crucial. RNase H1 is involved in the effects of DNA-like ASOs, and data suggest that there might be other RNase H enzymes in mammalian cells that contribute to the activity of DNA-like ASOs. Anticancer drugs: Overexpression of the c-MYC proto-oncogene is a potential target for anticancer agents. Hurley and colleagues report on a unique mutational mechanism for overexpression of c-MYC in human colorectal cancers and highlight a strategy that might allow the consequences of this mutational event to be reversed. G-quadruplex structures function as a negative regulator of c-MYC expression, and G-to-A mutations at specific positions within the G-quadruplex destabilize this structure and lead to increased expression of c-MYC. The study found that 6 out of 21 samples carried mutations that disrupt the G-quadruplex of the c-MYC promoter, while no such mutations were found in normal surrounding tissue. These findings indicate that the destabilizing mutations are positively selected for in cancer cells during the evolution of tumours, through the effects they have on c-MYC expression. The study also shows that TMPyP4 can stabilize G-quadruplexes and reduce expression of c-MYC, and that in cells with lower levels of NM23-H2, stabilization by TMPyP4 was enhanced. This work suggests a novel potential approach to the modulation of the expression of c-MYC, a key gene underlying a range of cancer types.Pharmacogenetics: EGFR mutations in lung cancer are linked to response to gefitinib therapy. Studies show that patients with non-small cell lung cancer who respond to gefitinib often have mutations in the epidermal growth factor receptor (EGFR). These mutations are found in the ATP-binding pocket of the tyrosine kinase domain of EGFR and are associated with increased sensitivity to gefitinib. Eight out of nine patients with gefitinib-responsive lung cancer had these mutations, while none of the seven nonresponders did. 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. HIV-1: Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir 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: The role of the human Rnase H1 in the pharmacology of DNA-like antisense drugs is crucial. RNase H1 is involved in the effects of DNA-like ASOs, and data suggest that there might be other RNase H enzymes in mammalian cells that contribute to the activity of DNA-like ASOs. Anticancer drugs: Overexpression of the c-MYC proto-oncogene is a potential target for anticancer agents. Hurley and colleagues report on a unique mutational mechanism for overexpression of c-MYC in human colorectal cancers and highlight a strategy that might allow the consequences of this mutational event to be reversed. G-quadruplex structures function as a negative regulator of c-MYC expression, and G-to-A mutations at specific positions within the G-quadruplex destabilize this structure and lead to increased expression of c-MYC. The study found that 6 out of 21 samples carried mutations that disrupt the G-quadruplex of the c-MYC promoter, while no such mutations were found in normal surrounding tissue. These findings indicate that the destabilizing mutations are positively selected for in cancer cells during the evolution of tumours, through the effects they have on c-MYC expression. The study also shows that TMPyP4 can stabilize G-quadruplexes and reduce expression of c-MYC, and that in cells with lower levels of NM23-H2, stabilization by TMPyP4 was enhanced. This work suggests a novel potential approach to the modulation of the expression of c-MYC, a key gene underlying a range of cancer types.