Maximization of growth rate is an important fitness strategy for bacteria. Bacteria can achieve this by expressing proteins at optimal concentrations, such that resources are not wasted. This is exemplified for Escherichia coli by the increase of its ribosomal protein-fraction with growth rate, which precisely matches the increased protein synthesis demand. These findings and others have led to the hypothesis that E. coli aims to maximize its growth rate in environments that support growth. However, what kind of regulatory strategy is required for a robust, optimal adjustment of the ribosome concentration to the prevailing condition is still an open question. In the present study, we analyze the ppGpp-controlled mechanism of ribosome expression used by E. coli and show that this mechanism maintains the ribosomes saturated with its substrates. In this manner, overexpression of the highly abundant ribosomal proteins is prevented, and limited resources can be redirected to the synthesis of other growth-promoting enzymes. It turns out that the kinetic conditions for robust, optimal protein-partitioning, which are required for growth rate maximization across conditions, can be achieved with basic biochemical interactions. We show that inactive ribosomes are the most suitable ‘signal’ for tracking the intracellular nutritional state and for adjusting gene expression accordingly, as small deviations from optimal ribosome concentration cause a huge fractional change in ribosome inactivity. We expect to find this control logic implemented across fast-growing microbial species because growth rate maximization is a common selective pressure, ribosomes are typically highly abundant and thus costly, and the required control can be implemented by a small, simple network.
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.
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