Predicting Tumor Responses to Gefitinib and Erlotinib

0002 Streptococcus pneumoniae is a common bacterium that is present in the nasopharynx of many children and some adults, where it causes no harm to its carrier but can be transmitted to others. If it moves beyond the nasopharynx, however, it can cause ear infections or invasive disease, such as pneumonia or meningitis. Invasive disease from this organism occurs especially in children, the elderly, and individuals with weakened immune systems. The protective effect of antibodies against bacterial pneumonia has been appreciated since the 1930s, when it was shown that serum therapy—the transfer of serum from an immunized animal to a patient with acute disease caused by the same bacterial strain—could reduce mortality from pneumococcal pneumonia by half. Subsequent development of vaccines based on the bacterium’s polysaccharide capsule, which could protect against infection, confi rmed that an endogenous antibody response can provide protection against invasive disease. One challenge for vaccine development has been the existence of many different serotypes (the same species of bacteria but with different composition of the polysaccharide capsule). As protection usually doesn’t extend to different Rethinking Immunity against Pneumococcal Disease DOI: 10.1371/journal.pmed.0020020 Tyrosine kinases regulate signaling pathways that control cell growth, proliferation, motility, and other critical cellular processes. Mutations in tyrosine kinase genes can lead to abnormal kinase activity, and some tumors become dependent upon this activity for growth and survival. Thus, kinases are attractive targets for anti-cancer drugs. Examples of new kinase inhibitors include gefi tinib and erlotinib, which have recently shown promise in treating non-small-cell lung cancer. Unfortunately, gefi tinib and erlotinib work only in a subset of patients, and they can have severe side effects, albeit infrequently. So researchers have been trying to fi nd ways to predict who will benefi t from therapy with these drugs and who won’t. Following the work of Lynch et al. (N Engl J Med 350: 2129–2139) and Paez et al. (Science 304: 1497–1500), William Pao and colleagues have previously shown that the epidermal growth factor receptor (EGFR), a tyrosine kinase, is often mutated in non-small-cell lung cancers, and that tumors that harbor such mutations are sensitive to gefi tinib and erlotinib. In this new study, they focused on a signaling protein called KRAS, which functions downstream of many tyrosine kinases, including EGFR. The KRAS gene is also often mutated in lung cancers, but very few cancers have mutations in both EGFR and the KRAS gene. To fi nd out whether KRAS mutations could help to predict which patients would respond to gefi tinib or erlotinib, the researchers looked for mutations in EGFR and KRAS genes in 60 tumors for which sensitivity to either drug was known. They extended their earlier fi ndings that EGFR mutations (which were found in 17 of the tumors) were associated with sensitivity to the kinase inhibitors, and found that tumors that had mutations in KRAS (a total of nine) were refractory (i.e., did not respond) to either drug. These results need to be validated in larger and prospective trials that use standardized mutation detection techniques. If they are confi rmed, knowing the mutation status of EGFR and KRAS in tumors could help physicians decide which patients should receive gefi tinib and/or erlotinib. As Inoue and Nukiwa state in a Perspective that accompanies the article, “By combining all the factors that relate to response or resistance, patients who will benefi t from treatment can hopefully be identifi ed. Undoubtedly we have taken a great step forward in molecular therapy for lung cancer treatment.”