mTOR Signaling Confers Resistance to Targeted Cancer Drugs

The clinical benefit of targeted cancer drugs is limited owing to intrinsic or adaptive resistance. Mechanisms of resistance can be cancer cell-autonomous or non cell-autonomous. Drugs can alter the tumor microenvironment, resulting in dynamic rewiring of signaling circuits and resistance in neighboring cancer cells. mTOR signaling is a major compensatory pathway allowing cancer cells to escape the effects of targeted drugs. mTOR inhibitors should be considered as a co-therapy to prevent resistance to other targeted cancer drugs. Phosphoproteomics is a novel approach for elucidating mechanisms of resistance to targeted therapies. Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy. Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy.