Abstract
Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity.
Highlights
Cancer is usually driven by an accumulation of genetic and epigenetic alterations which promote cell growth and immune escape
Among the different signaling pathways that transmit extracellular signals to mammalian target of rapamycin complex-1 (mTORC1), oncogenic PI3K/AKT and RAS/RAF/MEK/MAPK pathways have been well characterized. Activation of these pathways leads to the phosphorylation and inhibition of TSC2 which, in association with TSC1, forms a protein complex that inhibits mTORC1 [10,11,12]
This study further showed that genetic intratumor heterogeneity is associated with a functional heterogeneity of mTORC1 kinase activity and possibly sensitivity to mTORC1 inhibitors [32]
Summary
Cancer is usually driven by an accumulation of genetic and epigenetic alterations which promote cell growth and immune escape. In addition to tumor heterogeneity, development of cellular resistance to a specific treatment represents a major hurdle to targeted therapies in cancer. Among the different signaling pathways that transmit extracellular signals to mTORC1, oncogenic PI3K/AKT and RAS/RAF/MEK/MAPK pathways have been well characterized Activation of these pathways leads to the phosphorylation and inhibition of TSC2 which, in association with TSC1, forms a protein complex that inhibits mTORC1 [10,11,12]. Rapamycin and its derivatives termed rapalogs are the first generation of mTORC1 inhibitors They inhibit mTORC1 by binding together with FKBP12 to the FRB domain, a domain adjacent to the kinase domain of mTOR, limiting the access of substrates to the active kinase site [27, 28]. A third generation of mTOR inhibitor was developed, called Rapalink, containing rapamycin crosslinked with a kinase inhibitor of mTOR in the same molecule [32]
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