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Closing escape routes: inhibition of IL-8 signaling enhances the anti-tumor efficacy of PI3K inhibitors.

Juvekar A, Wulf GM - Breast Cancer Res. (2013)

Bottom Line: However, as is increasingly observed with inhibitors of cell signaling, there appear to be mechanisms of primary and secondary resistance.Britschgi and colleagues report that compensatory activation of the IL-8 signaling axis is a mechanism of primary resistance to PI3K inhibitors in some triple-negative breast cancers.Their paper lends further support to the concept that successful design of treatments with signal transduction inhibitors must anticipate potential escape routes - and include agents to simultaneously block them.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
The phosphoinositide 3-kinase (PI3K) pathway serves as a relay where signals that emanate from the cell membrane are received and converted into intracellular signals that promote proliferation and survival. Inhibitors of PI3K hold promise for the treatment of breast cancer because activation of this pathway is highly prevalent. However, as is increasingly observed with inhibitors of cell signaling, there appear to be mechanisms of primary and secondary resistance. Britschgi and colleagues report that compensatory activation of the IL-8 signaling axis is a mechanism of primary resistance to PI3K inhibitors in some triple-negative breast cancers. In a set of experiments that carefully emulate the clinical scenario in a mouse model, they show that simultaneous inhibition of Janus kinase 2 enhances the efficacy of PI3K/mammalian target of rapamycin inhibition. Their paper lends further support to the concept that successful design of treatments with signal transduction inhibitors must anticipate potential escape routes - and include agents to simultaneously block them.

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Resistance to combined phosphoinositide 3-kinase and mammalian target of rapamycin inhibition. Resistance to combined phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibition occurs in a two-wave mechanism. Initially, blockade of PI3K and mTOR lead to diversion of mitogenic serine/threonine phosphorylation via Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (Stat5). Stat5 activation then induces transcriptional changes with activation of the IL-8 signaling axis. In this process, tumor cells secrete IL-8 that then stimulates tumor cells via the G-protein coupled receptor CXCR1. PI3K and mTOR inhibition thus diverts mitogenic signaling to a new feed-forward loop that sustains tumor cell growth via IL-8 signaling. IGF-1, insulin-like growth factor-1; PKB, protein kinase B; TSC, tuberous sclerosis protein.
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Figure 1: Resistance to combined phosphoinositide 3-kinase and mammalian target of rapamycin inhibition. Resistance to combined phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibition occurs in a two-wave mechanism. Initially, blockade of PI3K and mTOR lead to diversion of mitogenic serine/threonine phosphorylation via Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (Stat5). Stat5 activation then induces transcriptional changes with activation of the IL-8 signaling axis. In this process, tumor cells secrete IL-8 that then stimulates tumor cells via the G-protein coupled receptor CXCR1. PI3K and mTOR inhibition thus diverts mitogenic signaling to a new feed-forward loop that sustains tumor cell growth via IL-8 signaling. IGF-1, insulin-like growth factor-1; PKB, protein kinase B; TSC, tuberous sclerosis protein.

Mentions: Britschgi and colleagues show that inhibition of PI3K not only rewires intracellular signaling but also leads cancer cells to recruit alternate extracellular signaling mechanisms to circumvent PI3K (Figure 1). This inhibition occurs in a two-step process: within hours of exposure to the dual PI3K/mTOR inhibitor NVP-BEZ 235, TNBC cells responded with upregulation of insulin-receptor signaling and with its downstream effector IRS1 directly activating Janus kinase 2 (JAK2) and its substrate, the transcription factor signal transducer and activator of transcription 5 (STAT5). Presumably through changing the transcriptional profile of the cancer cells, STAT5 then causes a more sustained upregulation of the IL-8 signaling axis, including secretion of IL-8 and upregulation of its receptor CXCR1 that then takes over to maintain JAK2/STAT5 signaling (Figure 1). The net effect is that cancer cells which typically rely on receptor tyrosine kinases/PI3K signaling now shift to G-protein coupled receptors, in this case IL-8/CXCR1, to activate JAK2/STAT5 and to keep their mitotic machinery going. The biological significance of this stepwise transition from receptor tyrosine kinases/PI3K to G-protein coupled receptor/JAK2 mitogenic signaling is confirmed by the findings that concomitant blockade of PI3K/mTOR and IL-8 signaling could effectively decrease tumor growth and metastasis and improve disease-free and overall survival in mice.


Closing escape routes: inhibition of IL-8 signaling enhances the anti-tumor efficacy of PI3K inhibitors.

Juvekar A, Wulf GM - Breast Cancer Res. (2013)

Resistance to combined phosphoinositide 3-kinase and mammalian target of rapamycin inhibition. Resistance to combined phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibition occurs in a two-wave mechanism. Initially, blockade of PI3K and mTOR lead to diversion of mitogenic serine/threonine phosphorylation via Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (Stat5). Stat5 activation then induces transcriptional changes with activation of the IL-8 signaling axis. In this process, tumor cells secrete IL-8 that then stimulates tumor cells via the G-protein coupled receptor CXCR1. PI3K and mTOR inhibition thus diverts mitogenic signaling to a new feed-forward loop that sustains tumor cell growth via IL-8 signaling. IGF-1, insulin-like growth factor-1; PKB, protein kinase B; TSC, tuberous sclerosis protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672703&req=5

Figure 1: Resistance to combined phosphoinositide 3-kinase and mammalian target of rapamycin inhibition. Resistance to combined phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibition occurs in a two-wave mechanism. Initially, blockade of PI3K and mTOR lead to diversion of mitogenic serine/threonine phosphorylation via Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (Stat5). Stat5 activation then induces transcriptional changes with activation of the IL-8 signaling axis. In this process, tumor cells secrete IL-8 that then stimulates tumor cells via the G-protein coupled receptor CXCR1. PI3K and mTOR inhibition thus diverts mitogenic signaling to a new feed-forward loop that sustains tumor cell growth via IL-8 signaling. IGF-1, insulin-like growth factor-1; PKB, protein kinase B; TSC, tuberous sclerosis protein.
Mentions: Britschgi and colleagues show that inhibition of PI3K not only rewires intracellular signaling but also leads cancer cells to recruit alternate extracellular signaling mechanisms to circumvent PI3K (Figure 1). This inhibition occurs in a two-step process: within hours of exposure to the dual PI3K/mTOR inhibitor NVP-BEZ 235, TNBC cells responded with upregulation of insulin-receptor signaling and with its downstream effector IRS1 directly activating Janus kinase 2 (JAK2) and its substrate, the transcription factor signal transducer and activator of transcription 5 (STAT5). Presumably through changing the transcriptional profile of the cancer cells, STAT5 then causes a more sustained upregulation of the IL-8 signaling axis, including secretion of IL-8 and upregulation of its receptor CXCR1 that then takes over to maintain JAK2/STAT5 signaling (Figure 1). The net effect is that cancer cells which typically rely on receptor tyrosine kinases/PI3K signaling now shift to G-protein coupled receptors, in this case IL-8/CXCR1, to activate JAK2/STAT5 and to keep their mitotic machinery going. The biological significance of this stepwise transition from receptor tyrosine kinases/PI3K to G-protein coupled receptor/JAK2 mitogenic signaling is confirmed by the findings that concomitant blockade of PI3K/mTOR and IL-8 signaling could effectively decrease tumor growth and metastasis and improve disease-free and overall survival in mice.

Bottom Line: However, as is increasingly observed with inhibitors of cell signaling, there appear to be mechanisms of primary and secondary resistance.Britschgi and colleagues report that compensatory activation of the IL-8 signaling axis is a mechanism of primary resistance to PI3K inhibitors in some triple-negative breast cancers.Their paper lends further support to the concept that successful design of treatments with signal transduction inhibitors must anticipate potential escape routes - and include agents to simultaneously block them.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
The phosphoinositide 3-kinase (PI3K) pathway serves as a relay where signals that emanate from the cell membrane are received and converted into intracellular signals that promote proliferation and survival. Inhibitors of PI3K hold promise for the treatment of breast cancer because activation of this pathway is highly prevalent. However, as is increasingly observed with inhibitors of cell signaling, there appear to be mechanisms of primary and secondary resistance. Britschgi and colleagues report that compensatory activation of the IL-8 signaling axis is a mechanism of primary resistance to PI3K inhibitors in some triple-negative breast cancers. In a set of experiments that carefully emulate the clinical scenario in a mouse model, they show that simultaneous inhibition of Janus kinase 2 enhances the efficacy of PI3K/mammalian target of rapamycin inhibition. Their paper lends further support to the concept that successful design of treatments with signal transduction inhibitors must anticipate potential escape routes - and include agents to simultaneously block them.

Show MeSH
Related in: MedlinePlus