Off-target resistance to TRK inhibitors

TRK inhibitors, like essentially all targeted therapies, are vulnerable to resistance mutations, and several resistance mutations to Vitrakvi (larotrectinib, Eli Lilly and Co.) and the recently approved Rozlytrek (entrectinib, Roche Holding AG) have been described. The most common form of resistance to targeted therapies, and the only mechanisms that have been described for TRK inhibitors to date, are due to mutations in the target itself. Now, researchers at Memorial Sloan-Kettering Cancer Center have described resistance to TRK inhibitors that occurred due to activation of the MAP kinase (MAPK) pathway. Experimental modeling suggested that "up-front dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations," the authors wrote. "Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design." They reported their findings in the Aug. 12, 2019, online issue of Nature Medicine.

Chromatin problem linked to accelerated aging

Researchers at the University of Antwerpen and the Scientific Institute for Research and Healthcare have shown that mutations in histone H1E, a widely expressed linker histone, is linked to accelerated aging in humans. Histones, the proteins that comprise chromatin, are known for packaging DNA and influencing gene expression by making different genes more or less accessible to the transcription machinery. Previous work had shown that specific histone H1E mutations were linked to a syndrome whose full spectrum is still being discovered. In the new work, the team showed that "cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging." Their work appeared in the Aug. 22, 2019, issue of the American Journal of Human Genetics.

Forward genetics identifies new immune player

Researchers at the University of Texas Southwestern Medical Center have identified a new immune deficiency in mice caused by deficiency in a splicing protein. SNRNP40, which encodes a spliceosome subunit and is highly expressed in lymphoid cells, were viable unless protein production was below roughly 7% of normal levels, but such animals had high levels of splicing errors, mostly retained introns, in hundreds of proteins and showed increased "susceptibility to infection by murine cytomegalovirus and multiple defects of lymphoid development, stability and function," the authors wrote. "The high level of conservation between human and mouse SNRNP40 protein sequences raises the possibility that viable hypomorphic mutations of SNRNP40 may in some cases also be responsible for immune dysfunction in humans." They reported their findings in the Aug. 19, 2019, online issue of Nature Immunology.

Metastasizing cells create their own hypoxia

Metastasizing cancer cells protect themselves in several ways when they pull up stakes from the primary tumor, including clustering and changing their metabolism to better defend against reactive oxygen species (ROS). Now, researchers at the Francis Crick Institute have discovered a molecular link between those two protective mechanisms. The team showed that when metastasizing tumor cells clustered, it induced a hypoxic environment, which led to enhanced clearance of damaged mitochondria and reduced ROS production. However, because they had fewer mitochondria, clustered cells had to rely on glycolysis to produce ATP. "Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo," the authors wrote. "Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities." They published their findings in the Aug. 22, 2019, issue of Cell Metabolism.

Neutrophils stick with dipeptidase in lung, liver

In inflammatory conditions, neutrophils converge on the sites of inflammation from the bloodstream and latch onto their target organs. In many target organs, they do so by binding to members of two specific protein families, selectins and integrins. They do not use those proteins, however, in the lung, where inflammation can cause acute respiratory distress syndrome (ARDS). Researchers at the University of Calgary have identified the enzyme dipeptidase-1 (DPEP-1) as the adhesion receptor for neutrophils during inflammation of the lung, as well as the liver. The team showed that this adhesive effect did not depend on DPEP-1's enzymatic activity. "Genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival" in animal models of sepsis, the authors wrote. "Our data establish DPEP-1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs." They reported their findings in the Aug. 22, 2019, issue of Cell.

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