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|Ref Type||Journal Article|
|Authors||Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR|
|Title||A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.|
|Journal||The Biochemical journal|
|Date||2011 Aug 15|
|Abstract Text||Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|A66||PIK3CA inhibitor 19||A66 inhibits PIK3CA, preventing the activation of the PI3K signaling pathway and potentially inhibiting tumor cell proliferation (PMID: 21668414, PMID: 28360038).|
|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 H1047R||ovarian cancer||sensitive||A66||Preclinical - Cell line xenograft||Actionable||In a preclinical study, A66 delayed tumor growth in an ovarian cancer cell line xenograft model harboring PIK3CA H1047R (PMID: 21668414).||21668414|
|PIK3CA H1047R||Advanced Solid Tumor||sensitive||A66||Preclinical||Actionable||In a preclinical study, A66 delayed tumor growth in human tumor xenograft models harboring PIK3CA H1047R mutations (PMID: 21668414).||21668414|
|PIK3CA E545K||Advanced Solid Tumor||resistant||A66||Preclinical||Actionable||In a preclinical study, cancer cell lines harboring PIK3CA E545K did not demonstrate sensitivity to A66 in culture, in contrast with cells harboring PIK3CA H1047R (PMID: 21668414).||21668414|
|PTEN loss||glioblastoma||resistant||A66||Preclinical - Cell line xenograft||Actionable||In a preclinical study, A66 did not inhibit tumor growth in a PTEN-null cell line xenograft model of glioblastoma (PMID: 21668414).||21668414|