The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP3 production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

Thirty-three-year-old Caucasian male underwent initiation of levetiracetam following witnessed generalized seizure activity at the same time presenting with a right MCA territory ischemic stroke. He then developed elevated CPK and myalgias are highly suspicious for rhabdomyolysis following levetiracetam. Subsequent improvement noted following complete cessation of medication. At follow-up patient reported complete resolution of hemiparesis and myalgias and no new neurological deficits while tolerating valproic acid. This case exemplifies potential rare adverse effect of levetiracetam. Levetiracetam is an antiepileptic medication effective for both generalized and focal types of epilepsy by affecting a broad spectrum of neurotransmitter release via calcium channels GABA receptors and synaptic vessel protein 2A (SV2A). Typical adverse effects include mild dizziness, headache, nausea, somnolence and sometimes hostility. This case provides further evidence of a rare and potentially life-threatening adverse effect of rhabdomyolysis. Further study is needed to possibly detect the exact mechanism resulting in this rare and dangerous adverse effect.

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