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|Ref Type||Journal Article|
|Authors||Tzenaki N, Andreou M, Stratigi K, Vergetaki A, Makrigiannakis A, Vanhaesebroeck B, Papakonstanti EA|
|Title||High levels of p110δ PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110δ inhibitors through PTEN activation.|
|Journal||FASEB journal : official publication of the Federation of American Societies for Experimental Biology|
|Abstract Text||Class IA PI3K isoforms have divergent, nonredundant cell biological roles. In untransformed cells and tissues, p110α and p110β are ubiquitously expressed, whereas p110δ expression is highly enriched in leukocytes. High levels of p110δ expression have been documented in some solid tumor cell lines, but the functional role is unknown. This study aimed to elucidate the link between elevated expression of p110δ PI3K and cancer. We report that in breast and prostate cancer cells that contain leukocyte levels of p110δ, p110δ activity dampens the activity of the PTEN tumor suppressor. Indeed, inactivation of p110δ in these cells led to PTEN activation, suppression of Akt phosphorylation, and inhibition of cell proliferation, with inhibition of PTEN activity being able to counterbalance p110δ inactivation. Likewise, forced overexpression of p110δ in cells with low p110δ expression reduced PTEN activity, resulting in increased Akt phosphorylation. Our data indicate that the oncogenic potential of p110δ PI3K overexpression might at least partially act through PTEN inactivation, and that p110δ-selective PI3K inhibitors can have a dual antitumor mechanism, namely by directly inhibiting p110δ signaling and by a broader inhibition of class I PI3K activity through PTEN activation. These data may have important implications in the intervention of breast cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|IC87114||IC-87114|IC 87114||PIK3CD inhibitor 26||IC87114 is a small molecule selective PIK3CD inhibitor, which may result in decreased tumor cell survival (PMID: 23275335, PMID: 22391131, PMID: 29236327).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA E545K||cervical cancer||sensitive||PW12||Preclinical||Actionable||In a preclinical study, PW12 inhibited proliferation of cervical cancer cells with a PIK3CA E545K mutation (PMID: 22391131).||22391131|