Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity

Figure 2

Factors impeding the anticancer efficacy of rapalogs. Treatment resistant mutations of mTOR: mutations of the FRB domain of mTOR block the binding of rapamyicn-FKBP12 to mTOR and impede the anticancer efficacy of rapalogs. Mutations conferring a hyperactive state of mTOR that resists ATP-competitive inhibitors of mTOR have also been reported. Activation of alternate proliferation pathways: upon inhibition of mTORC1, negative feedback loops are abolished, leading to an overactivation of PI3K/AKT and RAS/RAF/MEK/MAPK pathways that counteract the anticancer efficacy of rapalogs. Genetic heterogeneity: cancer cells harboring genetic mutations that lead to mTORC1 overactivation coexist with cancer cells displaying low mTORC1 activity. The latter exhibit an mTORC1-independent growth and are therefore resistant to mTORC1 inhibition. Hypoxia: hypoxia inhibits mTORC1; hence mTORC1 activity is reduced in hypoxic tumor regions, and these regions are resistant to mTORC1 inhibitors. Acidity: acidity inhibits mTORC1 activity in cancer cells in vitro, resulting in mTORC1-independent cancer cell growth. Functional heterogeneity: mTORC1 activity towards its downstream effectors is heterogeneous, where cancer cells displaying and phosphorylation patterns coexist in the same tumor. Rapalogs do not completely block mTORC1 activity with mTORC1-mediated 4E-BP1 phosphorylation being in part resistant to rapalogs. Beige squares and green ovals symbolize cancer cells and black ovals symbolize nuclei. Dark green: high mTORC1 activity; light green: low mTORC1 activity. Functionally active components of intracellular signaling pathways are displayed in black writing; functionally inactive components of intracellular signaling pathways are displayed in grey writing.