What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors.

Significance: There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer.

Figure 1

Inhibition of mTORC1 results in feedback PI3K activation. In the presence of increased PI3K activity p70/S6K provides basal negative feedback to PI3K signaling via phosphorylating IRS1 and targeting it for degradation, thus decreasing positive input into the PI3K pathway (A). In the presence of mTORC1 inhibition there is a decrease in p70/S6K-mediated IRS1 phosphorylation, thereby stabilizing the protein and allowing for positive input into the PI3K pathway (B). Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, PTEN; phosphatase and tensin homolog, IRS1; insulin receptor substrate 1, AKT; protein kinase B, mTORC1; mammalian target of rapamycin complex 1, S6K1; ribosomal protein S6 kinase, 4E-BP1; Eukaryotic translation initiation factor 4E-binding protein 1, eIF4E; eukaryotic translation initiation factor 4-E.

Figure 1

Inhibition of mTORC1 results in feedback PI3K activation. In the presence of increased PI3K activity p70/S6K provides basal negative feedback to PI3K signaling via phosphorylating IRS1 and targeting it for degradation, thus decreasing positive input into the PI3K pathway (A). In the presence of mTORC1 inhibition there is a decrease in p70/S6K-mediated IRS1 phosphorylation, thereby stabilizing the protein and allowing for positive input into the PI3K pathway (B). Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, PTEN; phosphatase and tensin homolog, IRS1; insulin receptor substrate 1, AKT; protein kinase B, mTORC1; mammalian target of rapamycin complex 1, S6K1; ribosomal protein S6 kinase, 4E-BP1; Eukaryotic translation initiation factor 4E-binding protein 1, eIF4E; eukaryotic translation initiation factor 4-E.

Figure 2

HER2 and PI3K-targeted therapies result in FOXO3a-mediated feedback up-regulation of HER3 and IGF-1R and provide an escape from PI3K pathway inhibition. In the basal state AKT-mediated FOXO3a phosphorylation inhibits translocation of FOXO3a to the nucleus and provides a basal inhibition of RTK synthesis (A). In the presence of PI3K inhibition, via either upstream RTK blockade or small molecule inhibitors, decreased AKT activity allows FOXO3a to translocate to the nucleus and effect transcription of FOXO3a target genes, including HER3 and IGF-1R (B). The increased RTK expression mediates resistance to PI3K inhibition via increasing input into the PI3K pathway and alternate growth pathways including MAPK. Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, PTEN; phosphatase and tensin homolog, IRS1; insulin receptor substrate 1, AKT; protein kinase B, mTORC1; mammalian target of rapamycin complex 1, HER2; human epidermal growth factor receptor 2, HER3; human epidermal growth factor receptor 3, IGF-1R; insulin-like growth factor 1 receptor, FOXO3a; forkhead box O3a.

Figure 2

HER2 and PI3K-targeted therapies result in FOXO3a-mediated feedback up-regulation of HER3 and IGF-1R and provide an escape from PI3K pathway inhibition. In the basal state AKT-mediated FOXO3a phosphorylation inhibits translocation of FOXO3a to the nucleus and provides a basal inhibition of RTK synthesis (A). In the presence of PI3K inhibition, via either upstream RTK blockade or small molecule inhibitors, decreased AKT activity allows FOXO3a to translocate to the nucleus and effect transcription of FOXO3a target genes, including HER3 and IGF-1R (B). The increased RTK expression mediates resistance to PI3K inhibition via increasing input into the PI3K pathway and alternate growth pathways including MAPK. Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, PTEN; phosphatase and tensin homolog, IRS1; insulin receptor substrate 1, AKT; protein kinase B, mTORC1; mammalian target of rapamycin complex 1, HER2; human epidermal growth factor receptor 2, HER3; human epidermal growth factor receptor 3, IGF-1R; insulin-like growth factor 1 receptor, FOXO3a; forkhead box O3a.

Figure 3

High nuclear β-catenin confers resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastases in colon cancer. Activation of the Wnt/β-catenin leads to nuclear accumulation of β-catenin, and activation of the PI3K-AKT pathway inhibits nuclear translocation of FOXO3a (A). The presence of high nuclear β-catenin and increased nuclear FOXO3a results in resistance to PI3K pathway inhibitors and promotes cell scattering and metastases (B). Reducing nuclear β-catenin through Wnt/β-catenin pathway inhibition reverses the metastatic potential and resistance to PI3K-AKT inhibitors, resulting in increased apoptosis (C). Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, AKT; protein kinase B, FOXO3a; forkhead box O3a, LEF; lymphoid enhancer factor, TCF; t-cell factor.

Figure 3

High nuclear β-catenin confers resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastases in colon cancer. Activation of the Wnt/β-catenin leads to nuclear accumulation of β-catenin, and activation of the PI3K-AKT pathway inhibits nuclear translocation of FOXO3a (A). The presence of high nuclear β-catenin and increased nuclear FOXO3a results in resistance to PI3K pathway inhibitors and promotes cell scattering and metastases (B). Reducing nuclear β-catenin through Wnt/β-catenin pathway inhibition reverses the metastatic potential and resistance to PI3K-AKT inhibitors, resulting in increased apoptosis (C). Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, AKT; protein kinase B, FOXO3a; forkhead box O3a, LEF; lymphoid enhancer factor, TCF; t-cell factor.

Figure 3

High nuclear β-catenin confers resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastases in colon cancer. Activation of the Wnt/β-catenin leads to nuclear accumulation of β-catenin, and activation of the PI3K-AKT pathway inhibits nuclear translocation of FOXO3a (A). The presence of high nuclear β-catenin and increased nuclear FOXO3a results in resistance to PI3K pathway inhibitors and promotes cell scattering and metastases (B). Reducing nuclear β-catenin through Wnt/β-catenin pathway inhibition reverses the metastatic potential and resistance to PI3K-AKT inhibitors, resulting in increased apoptosis (C). Dotted lines represent multiple steps not shown graphically, line strength represents relative activation. RTK; receptor tyrosine kinase, PI3K; phosphoinositide 3-kinase, AKT; protein kinase B, FOXO3a; forkhead box O3a, LEF; lymphoid enhancer factor, TCF; t-cell factor.