Efficacy of osimertinib against EGFRvIII+ glioblastoma.

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth in vitro and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers.

Genetic defects in the synaptic scaffolding protein gene, SHANK2, are linked to a variety of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and bipolar disorder, but the molecular mechanisms underlying the pleotropic effects of SHANK2 mutations are poorly understood. We generated and characterized a line of Shank2 mutant mice by deleting exon 24 (Δe24). Shank2Δe24-/- mice engage in significantly increased locomotor activity, display abnormal reward-seeking behavior, are anhedonic, have perturbations in circadian rhythms, and show deficits in social and cognitive behaviors. While these phenotypes recapitulate the pleotropic behaviors associated with human SHANK2-related disorders, major behavioral features in these mice are reminiscent of bipolar disorder. For instance, their hyperactivity was augmented with amphetamine but was normalized with the mood stabilizers lithium and valproate. Shank2 deficiency limited to the forebrain recapitulated the bipolar mania phenotype. The composition and functions of NMDA and AMPA receptors were altered at Shank2-deficient synapses, hinting toward the mechanism underlying these behavioral abnormalities. Human genetic findings support construct validity, and the behavioral features in Shank2 Δe24 mice support face and predictive validities of this model for bipolar mania. Further genetic studies to understand the contribution of SHANK2 deficiencies in bipolar disorder are warranted.