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PNAS Papers on KRAS-Mutated Lung Cancer, p53-Related Transcriptional Features, More

A team from Spain, China, Switzerland, and the US report on potential treatment targets and resistance mechanisms in KRAS-mutated forms of lung adenocarcinoma. Using genetically engineered mouse model experiments, pharmacological experiments, and other approaches, the team highlighted the potential for curbing lung adenocarcinoma growth by targeting RAF1 as well as cyclin-dependent kinases downstream of the MAP-kinase signaling pathway in advanced tumors driven by KRAS and p53. Even so, follow-up bioinformatic, gene expression, and methylation analyses on drug-resistant tumor cells pointed to potential resistance mechanisms, including enhanced methylation patterns and altered tumor suppressor gene activity, the authors report, though they suggest that "CDK4/RAF1-resistant cells can be pharmacologically controlled."

University of Texas MD Anderson Cancer Center researchers outline transcriptional features found in genetically engineered mouse models missing a p53 inhibitor called MDM2. The team relied on p53 chromatin immunoprecipitation sequencing experiments, combining the data with available RNA sequencing profiles for pancreas, small intestine, ovary, kidney, and heart tissues to identify tissue-specific and shared transcriptional signatures reflecting p53 activity, among other results. "Our study begins to uncover the commonalities and differences engrained in the tissue-specific and cell-specific p53 transcriptomes," the investigators write. "Gaining a better understanding of the wild-type p53 transcriptome will subsequently lead to determining the elusive combination of genes responsible for the tumor-suppressive function of p53."

A team led by investigators at the University of Connecticut and the Connecticut Children's Center for Rare Bone Disorders shares findings from mouse experiments aimed at finding ways to stem bone loss and dwindling skeletal muscles under low gravity conditions resembling those that astronauts experience in space. Based on their genetic and pharmacologic experiments, the researchers found that muscle and bone mass got a boost in mice missing the myostatin-coding gene MSTN that took a trip to the International Space Station. Likewise, they saw similar protective effects with inhibitors targeting the MSTN/activin A pathway. "We show that targeting this signaling pathway has significant beneficial effects in protecting against both muscle and bone loss in microgravity," the authors write, "suggesting that this strategy may be effective in preventing or treating muscle and bone loss not only in astronauts on prolonged missions but also in people with disuse atrophy on Earth, such as in older adults or in individuals who are bedridden or wheelchair-bound from illness."