Reference Detail

Ref Type

Journal Article

PMID

(21668414)

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	Vol	Issue	Date	Pages	Journal Short Title
The Biochemical journal	438	1	2011 Aug 15	53-62	Biochem J

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
A66	A66	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
A66			PIK3CA inhibitor 24	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
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
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 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
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