Reference Detail

Ref Type

Journal Article

PMID

(25349966)

Authors

Sathe A, Guerth F, Cronauer MV, Heck MM, Thalgott M, Gschwend JE, Retz M, Nawroth R

Title

Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer	111	11	2014 Nov 25	2103-13	Br J Cancer

URL

Abstract Text

Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response.Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation.Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PIK3CA	E674Q	missense	unknown	PIK3CA E674Q lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E674Q has been identified in the scientific literature (PMID: 25349966, PMID: 28760909), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, May 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA A1066V	urinary bladder cancer	resistant	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, a bladder cancer cell line harboring PIK3CA A1066V, along with KRAS and NRAS mutations, was resistant to MK2206 in culture (PMID: 25349966).	25349966
PIK3CA E545G	urinary bladder cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 increased apoptosis and inhibited viability in a bladder cancer cell line harboring PIK3CA E545G in culture (PMID: 25349966).	25349966
PIK3CA E545K	urinary bladder cancer	sensitive	MK2206	Preclinical - Cell line xenograft	Actionable	In a preclinical study, MK2206 increased apoptosis and inhibited viability in bladder cancer cell lines harboring PIK3CA E545K in culture and inhibited tumor growth in cell line xenograft models (PMID: 25349966).	25349966
PIK3CA E542K PIK3CA E674Q	urinary bladder cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 increased apoptosis and inhibited viability in a bladder cancer cell line harboring PIK3CA E542K and E674Q in culture (PMID: 25349966).	25349966
PIK3CA P124L	urinary bladder cancer	resistant	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, a bladder cancer cell line harboring PIK3CA P124L was resistant to MK2206 in culture (PMID: 25349966).	25349966