A functional genomic screen has revealed a new drug combination that boosts the efficacy of KRAS inhibitors for aggressive lung cancer. As reported in Science Translational Medicine, a team led by scientists from the Francis Crick Institute found that a combination of MEK enzyme and IGF1R receptor inhibitors, which shows promise for KRAS-mutant lung cancers in preclinical studies, could be further enhanced by the addition of an mTOR inhibitor. This cocktail blocks the principal signaling pathways required for the survival of KRAS-mutant cells and produced marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacement of the MEK inhibitor with a KRAS inhibitor called ARS-1620 eliminated the toxic side effects of MEK inhibition while proving even more effective in mouse models.
A large-scale RNA interference screen has identified a key regulator of mitochondrial morphology and tissue homeostasis. In a study appearing in Science Advances, investigators from Zhejiang University ran an RNAi screen covering roughly one-quarter of all Drosophila melanogastergenes, pinpointing 578 whose knockdown led to aberrant shapes or distributions of mitochondria. Further analysis showed that knocking down Dhpr — a gene encoding an enzyme catalyzing tetrahydrobiopterin regeneration — leads to a reduction in tyrosine hydroxylase neurons, shorter lifespan, and gradual loss of muscle integrity and climbing ability. Meanwhile, affected mitochondria in the Dhpr mutants were swollen and have fewer cristae. Overexpression of the gene rescued the mitochondrial defects.