Abstract:
UNLABELLED:Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms. SIGNIFICANCE:We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Ni J,Liu Q,Xie S,Carlson C,Von T,Vogel K,Riddle S,Benes C,Eck M,Roberts T,Gray N,Zhao Jdoi
10.1158/2159-8290.CD-12-0003subject
Has Abstractpub_date
2012-05-01 00:00:00pages
425-33issue
5eissn
2159-8274issn
2159-8290pii
2159-8290.CD-12-0003journal_volume
2pub_type
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