Targeting the mTOR pathway in idiopathic multicentric Castleman disease

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness of systemic inflammation and organ dysfunction, with unknown etiology. Although therapies targeting IL-6 have been proven effective, a subset of patients with iMCD are resistant to this approach. In this issue of the JCI, Fajgenbaum et al. performed an in-depth analysis of serum inflammatory markers in three iMCD patients refractory to IL-6 blockade, and identified activation of the mTOR pathway associated with symptom flares. Treatment with sirolimus, an mTOR inhibitor, induced remission in all three patients. This study models a precision medicine approach to discovering therapies for rare diseases.

Figure 1. Inhibition of the IL-6 and mTOR pathways in iMCD influences symptoms.

IL-6 and IL-6 receptor (IL-6R) associate with the signal transducer gp130, leading to dimerization and activation of the JAK/STAT signaling cascade. Siltuximab neutralizes IL-6 and tocilizumab blocks the IL-6R. Growth factor (GF) binds to the receptor tyrosine kinase (RTK) leading to downstream activation of PI3 kinase (PI3K), AKT, and ultimately mTOR. Sirolimus binds to the tacrolimus binding protein (FKBP), and together sirolimus and FKBP inhibit mTOR activity.