Jiang et al., pp. 2480–2486 About 20% of patients with non-small-cell lung cancer respond well to treatment with the tyrosine kinase inhibitors gefitinib and erlotinib. The success of these drugs is dependent on activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase, which trigger inappropriate activation of anti-apoptotic signaling pathways and uncontrolled cell proliferation. However, the vast majority of tumors that initially respond to the treatment eventually become resistant. Some of the relapsed tumors acquire a secondary EGFR mutation that prevents binding of the drugs to the tyrosine kinase domain. Others show amplification of the MET proto-oncogene that induces EGFR-independent activation of downstream effector molecules. In this issue of IJC, Jiang and colleagues report on the discovery of a new mechanism by which non-small-cell lung cancers evade tyrosine kinase inhibitor treatment. In a study of six matched pretreatment and post-therapeutic lesions they show that some tumors are genetically heterogeneous for EGFR mutations. In pretreatment samples, they detected tumor cell clones expressing EGFR with activating mutations but also clones expressing wild-type EGFR. Initially, the wild-type clones are rare. However, during gefitinib treatment these clones selectively survive whereas clones with activating EGFR mutations decrease or completely disappear. Their results indicate that resistance to gefitinib treatment is more complex than initially thought; screening for EGFR genetic heterogeneity may help identify those cancer patients who respond best to the therapy. D'Agostini et al., pp. 2497–2502 Secondhand cigarette smoke, also known as environmental cigarette smoke (ECS), is generated by the smoking end of a cigarette and the smoke exhaled by smokers. It is passively inhaled by nonsmokers and can cause a wide range of adverse health effects. Previous studies showed that long-term exposure to ECS increases the development of lung tumors, a phenomenon attributed mainly to the gas phase of ECS. This study by D'Agostini and colleagues now uncovers a compelling link between ECS and light exposure and demonstrates that the carcinogenic properties of ECS can reach far beyond the respiratory tract. The TLR10-TLR1-TLR6 gene cluster on chromosome 4p14 and the location of the 28 single nucleotide polymorphisms (SNPs) genotyped in this study. The six SNPs marked in bold were significantly associated with reduced risk of prostate cancer. The authors exposed newborn Swiss albino mice to ECS (63 mg/m3 total suspended particulate for 6 h) during the first 4 months of their life, a treatment that triggered preneoplastic lesions in the lung as expected. However, these lesions did not progress to lung tumors unless the mice were also exposed to UV-A and UV-B-containing light emitted by halogen quartz bulbs. Exposure to light alone had no carcinogenic effect. In addition, exposure to ECS caused histopathological alterations in extra-respiratory organs, especially in the form of parenchymatous dystrophy of the liver, microadenomas and adenomas in the renal pelvis and the kidney, and papillomas in the urinary bladder. The authors speculate that light and smoke synergize in inducing DNA damage in the respiratory tract. They further point out that the liver of newborns is less efficient in clearing toxic products, possibly explaining the multiorgan effects of ECS in this study. Stevens et al., pp. 2644–2650 One in six men in the United States develops prostate cancer in his lifetime. Although it is the most common cancer among men, the insight into the risk factors and molecular causes remain limited. Previous studies revealed an association between the risk to develop prostate cancer and genetic variations in Toll-like receptors (TLR). TLRs are members of the interleukin-1 receptor superfamily and are an essential component of the innate arm of the immune system. Associations between TLR4 or the TLR10-TLR1-TLR6 gene cluster and prostate cancer have been described before but the results are highly controversial. Stevens and colleagues studied more than 1400 men with prostate cancer and the same number of controls enrolled in the American Cancer Society Cancer Prevention II Nutrition Cohort. They identified six single nucleotide polymorphisms within the TLR10-TLR1-TLR6 gene cluster that were significantly associated with a reduced risk of prostate cancer. Associations were found regardless of whether all cases or only advanced cases were analyzed, suggesting that the genetic variation influenced the initial development of prostate cancer rather than the progression of the disease. These findings strengthen the etiological link between chronic inflammation and prostate cancer. TLR1 and TLR6 recognize bacterial triacylated and diacylated lipoproteins, respectively, when heterodimerized with TLR2. No ligand has been identified for TLR10. It remains unclear how altered TLR functions modulate cancer risks. Increased TLR function could enhance anticancer immunity. Decreased activity may allow cancer cells to escape immune detection and elimination.