The new finding of PI3K signaling regulation provides a novel therapeutic strategy for luminal breast cancer

 

Phosphatidylinositol 3-kinase (PI3K) lipid kinases are an ubiquitous kinases that mediate cell proliferation and growth, as well as development and progress of many types of tumors. The inhibition of p110α, the alpha isoform of PI3K catalytic subunit (p110a), by BYL719 is used as therapeutic strategy for suppression tumor progression. Costa et al. found the high efficiency of p110α inhibition is attenuated by p110β accumulation. The article was published in Cancer Cell, recently.

 

BYL719, a selective p110α inhibitor, has been tested in the clinic for breast cancer with PIK3CA mutations and/or HER2 amplification, which is sensitive to the drug. However, researchers found PI3K signaling was re-accumulated following initial inhibitory effect of BYL719. Mechanically, the PI3K restoration is result from the activation of the p100β isoform, which limits the efficiency of BYL719 on suppression cancer cell growth, even among the sensitive cancers. Generally, the phosphorylation level of the downstream molecule AKT is used to measure the activity of PI3K due to the difficulty of directly measuring PIP₃, the product of PI3K. However, the p110β-mediated re-accumulation of PI3K does not restore AKT phosphorylation. In summary, the findings reveal a new mechanism of PI3K-AKT signaling regulation in response to BYL719, demonstrate the combination of p110β inhibitor with BYL719 may act as a potential novel therapeutic strategy for treating breast cancer with PIK3CA mutations and/or HER2 amplification.

 

Reference:
Cancer Cell. 2015 Jan 12;27(1):97-108.

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