Feedback Suppression of PI3Kα Signaling in PTEN-Mutated Tumors Is Relieved by Selective Inhibition of PI3Kβ

Abstract

SUMMARY In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.

A cancer pharmacogenomic screen powering crowd-sourced advancement of drug combination prediction

“…The apparent antagonism, however, suggests feedback following PIK3CB/D inhibition enhances mutant PIK3CA expression/activity. Indeed PIK3CB inhibition has been shown to result in elevated expression and activity of PIK3CA 39 , and may also relieve the inhibitory effects of substrate competition or dimerization between PIK3CA and PIK3CB/D.…”

Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models

“…Differences in both lipid-and protein-kinase activities have been described for PI3K p110 isoforms (50,51), which allow precise control over downstream transduction in response to activating signals. In addition, rebound signalling in other pathways following inhibition of dominant signalling isoforms has been identified in various cell lines (52,53), demonstrating the adaptive nature of cancer cell signalling pathways and consequent cell survival.…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Network wiring from RTK to PIK3CA/mTOR and MEK/ERK signaling is reasonably well understood; however, the influence of genetic alterations found in neuroendocrine tumors, including TSC2, AKT and PTEN alterations onto network behavior during therapeutic interference is unknown and is currently explored in NET (http://www.sys-med.de/ de/demonstratoren/maptor-net). Recently published experimental work provided novel ideas on how network behavior in the context of specific genetic alterations can have an influence on therapy (François et al 2015, Schwartz et al 2015, Soler et al 2016, Xu et al 2016. Selective inhibition of PIK3CAβ in PTEN-deficient cancers results only in a transient suppression of AKT/mTOR activity due to feedback-dependent activation of RTKs and subsequent activation of PIK3CAα (Schwartz et al 2015).…”

“…Recently published experimental work provided novel ideas on how network behavior in the context of specific genetic alterations can have an influence on therapy (François et al 2015, Schwartz et al 2015, Soler et al 2016, Xu et al 2016. Selective inhibition of PIK3CAβ in PTEN-deficient cancers results only in a transient suppression of AKT/mTOR activity due to feedback-dependent activation of RTKs and subsequent activation of PIK3CAα (Schwartz et al 2015). On the contrary, PIK3CAα inhibition in tumors harboring RTK or PI3K mutations resulted in PIK3CAβ activation.…”