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. Author manuscript; available in PMC: 2018 Aug 10.
Published in final edited form as: Cell. 2017 Aug 10;170(4):605–635. doi: 10.1016/j.cell.2017.07.029

Figure 6. Mechanisms of Adaptive, Primary, and Acquired Resistance to PI3K/mTOR Pathway Inhibitors.

Figure 6

Adaptive resistance (in green, also labeled “1”) often involves upregulation of upstream regulators, including RTKs (HER3, INSR, IGF-1R), IRS-1, JAK2, or SRC by disruption of negative-feedback loops. Primary or acquired resistance (in red, “2”) can arise by expression or activation of kinases with downstream targets in common with AKT or mTORC1 (SGK1, PDK1, PIM1), constitutive activation of mTORC1 signaling (e.g., due to loss of TSC function), or loss of PTEN expression. Primary or acquired resistance (in orange, “3”) can also arise by PI3K isoform switching; selective inhibition of p110α can lead to substitution by p110β or vice versa. Finally, primary or acquired resistance can also arise by activation of heterologous pathways leading to common endpoints; for instance, MYC-dependent transcriptional activation or ERK activity (in pink, “4”).