In Science Signaling this week, researchers in the UK say amplification of oncogenes KRAS or BRAF underpins an acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. The researchers modeled acquired resistance to the MEK 1/2 inhibitor selumetinib in colorectal cancer cells with BRAF or KRAS mutations. Genomic sequencing showed no acquired mutations in MEK1 or MEK2, selumetinib's primary targets. "Rather, resistant lines showed a marked up-regulation of their respective driving oncogenes, BRAF600E or KRAS13D, due to intrachromosomal amplification," the authors write. "Inhibition of BRAF reversed resistance to [selumetinib] in COLO205 cells, which suggested that combined inhibition of MEK1/2 and BRAF may reduce the likelihood of acquired resistance in tumors with BRAF600E."
In Science Translational Medicine this week, an international team of researchers are using mutant-specific ion channel characteristics to stratify risk in long QT syndrome patients. By correlating the clinical phenotype of 387 long QT patients with the cellular electrophysiological characteristics caused by an array of mutations in KCNQ1, the team found that "channels with a decreased rate of current activation are associated with increased risk of cardiac events, independent of the clinical parameters usually used for risk stratification." These results show that genotype and biophysical phenotype analysis can be useful for stratification of patients and that slow channel activation is associated with an increased risk of cardiac events, the researchers say.
In Science this week, researchers in Europe, the US, South America, and North Africa present their findings on chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. The researchers report two genetic etiologies of chronic mucocutaneous candidiasis disease — "autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A, and autosomal dominant deficiency of the cytokine interleukin-17F." These results show that human IL-17A and IL-17F are essential for immunity against C. albicans, but otherwise "largely redundant," the team says.
Also in Science this week, Elizabeth Pennisi says mouse and human studies are beginning to clarify the role of gut bacteria in obesity. Research on mice has shown that when microbes from obese mice are transplanted into the gut of lean mice, the lean mice become fat, Pennisi says. Now researchers are focused on seeing if the same thing applies to people. Scientists are also looking at antibiotic use, particularly in children, to see how it might affect the long-term establishment of a "balanced microbial community in the human gut, eliminating bacteria there that could help ward off obesity," she adds.