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. Author manuscript; available in PMC: 2014 Jul 31.
Published in final edited form as: Nat Rev Drug Discov. 2014 Feb;13(2):140–156. doi: 10.1038/nrd4204

Figure 3. Two arguments for combining TKIs with PI3K/AKT/mTOR inhibitors.

Figure 3

Left: In cancers driven by activated tyrosine kinases, TKI resistance can develop through alternative pathways that maintain PI3K signaling such as compensatory growth factor (GF) receptors, PTEN loss, PIK3CA mutation or RAS activation. Combined targeting of PI3K can prevent or overcome drug resistance. Right: In cancers driven by lesions in PI3K or PTEN, inhibiting PI3K or AKT or TORC1/TORC2 can cause elevated GF receptor signaling through FOXO-dependent gene expression. Adding a TKI can ameliorate this compensatory signaling mechanism.

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