Molecular Pathways: Increased Susceptibility to Infection Is a Complication of mTOR Inhibitor Use in Cancer Therapy

Adrian M. Eiden, Shuling Zhang, Joy M. Gary, John K. Simmons, Beverly A. Mock

As one of the earliest examples of "chemical biology," the Mechanistic Target of Rapamycin (mTOR) protein and its chemical inhibitors have been extensively studied across a spectrum of physiological and pathological processes at the molecular, organismal, and patient population levels. There are several FDA-approved mTOR inhibitors (sirolimus, everolimus and temsirolimus) with indications for cancer treatment and for prevention of solid organ rejection. Dozens of mTOR inhibitors are currently being evaluated in hundreds of on-going clinical trials across a spectrum of diseases, including numerous cancer indications, autoimmune diseases, and a number of congenital disorders. As many of the approved and investigational indications for mTOR inhibitors require long-term treatment, the magnitude and incidence of particular side effects differs from those observed in shorter-term treatments. Here, we focus on the particular increased risk of infections while receiving mTOR inhibitors. While increased infection rates might be expected from a class of drugs approved as post-transplant immunosuppressants, we review reports from clinical, mechanistic, and genetically engineered mouse model (GEMM) studies detailing a much more nuanced view of mTOR inhibitor drug action and target biology.