Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : firstname.lastname@example.org
|Ref Type||Journal Article|
|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.|
|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.|
|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, Nov 2023).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|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 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 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|
|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|