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Ref Type Journal Article
PMID (22932669)
Authors Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, Miller TW, Arteaga CL, Mills GB, Gonzalez-Angulo AM, Meric-Bernstam F
Title Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 18
Issue 20
Date 2012 Oct 15
URL
Abstract Text We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity.MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel.MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206-sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo.MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials.

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Molecular Profile Treatment Approach
PTEN Q298fs Akt Inhibitor (Pan)
PTEN P339L Akt Inhibitor (Pan)
PTEN C211W Akt Inhibitor (Pan)
PTEN T319* Akt Inhibitor (Pan)
PTEN S170N Akt Inhibitor (Pan)
PTEN G129V Akt Inhibitor (Pan)
PTEN Y27D Akt Inhibitor (Pan)
PTEN L57fs Akt Inhibitor (Pan)
PTEN D252G Akt Inhibitor (Pan)
PTEN L247Sfs*6 Akt Inhibitor (Pan)
PTEN A126fs Akt Inhibitor (Pan)
PTEN R130P Akt Inhibitor (Pan)
PTEN Y155N Akt Inhibitor (Pan)
PTEN F90S Akt Inhibitor (Pan)
PTEN D92E Akt Inhibitor (Pan)
PTEN D107G Akt Inhibitor (Pan)
PTEN R74Dfs*25 Akt Inhibitor (Pan)
PTEN H123Q Akt Inhibitor (Pan)
PTEN F56fs Akt Inhibitor (Pan)
PTEN G143fs Akt Inhibitor (Pan)
PTEN S59* Akt Inhibitor (Pan)
PTEN R15I Akt Inhibitor (Pan)
PTEN T167N Akt Inhibitor (Pan)
PTEN G132D Akt Inhibitor (Pan)
PTEN V317fs Akt Inhibitor (Pan)
PTEN V133I Akt Inhibitor (Pan)
PTEN G127N Akt Inhibitor (Pan)
PTEN V166Sfs*14 Akt Inhibitor (Pan)
PTEN D116fs Akt Inhibitor (Pan)
PTEN F241fs Akt Inhibitor (Pan)
PTEN E288* Akt Inhibitor (Pan)
PTEN Y76fs Akt Inhibitor (Pan)
PTEN D24V Akt Inhibitor (Pan)
PTEN R130A Akt Inhibitor (Pan)
PTEN G129D Akt Inhibitor (Pan)
PTEN R130fs Akt Inhibitor (Pan)
PTEN V119fs Akt Inhibitor (Pan)
PTEN M35V Akt Inhibitor (Pan)
PTEN C136R Akt Inhibitor (Pan)
PTEN L108P Akt Inhibitor (Pan)
PTEN E291* Akt Inhibitor (Pan)
PTEN M199del Akt Inhibitor (Pan)
PTEN E242fs Akt Inhibitor (Pan)
PTEN K237fs Akt Inhibitor (Pan)
PTEN D24N Akt Inhibitor (Pan)
PTEN Q245* Akt Inhibitor (Pan)
PTEN N212Kfs*10 Akt Inhibitor (Pan)
PTEN Y65C Akt Inhibitor (Pan)
PTEN K6fs Akt Inhibitor (Pan)
PTEN R15K Akt Inhibitor (Pan)
PTEN Q261* Akt Inhibitor (Pan)
PTEN D92A Akt Inhibitor (Pan)
PTEN G251D Akt Inhibitor (Pan)
PTEN F21A Akt Inhibitor (Pan)
PTEN I101F Akt Inhibitor (Pan)
PTEN M35R Akt Inhibitor (Pan)
PTEN A126G Akt Inhibitor (Pan)
PTEN T167A Akt Inhibitor (Pan)
PTEN T131fs Akt Inhibitor (Pan)
PTEN K62R Akt Inhibitor (Pan)
PTEN I101T Akt Inhibitor (Pan)
PTEN D92H Akt Inhibitor (Pan)
PTEN R161G Akt Inhibitor (Pan)
PTEN L265fs Akt Inhibitor (Pan)
PTEN S302Afs*5 Akt Inhibitor (Pan)
PTEN N340fs Akt Inhibitor (Pan)
PTEN F154L Akt Inhibitor (Pan)
PTEN K13E Akt Inhibitor (Pan)
PTEN V54fs Akt Inhibitor (Pan)
PTEN C124S Akt Inhibitor (Pan)
PTEN K6I Akt Inhibitor (Pan)
PTEN H61D Akt Inhibitor (Pan)
PTEN G127E Akt Inhibitor (Pan)
PTEN C124G Akt Inhibitor (Pan)
PTEN K289Nfs*8 Akt Inhibitor (Pan)
PTEN Y155C Akt Inhibitor (Pan)
PTEN V343E Akt Inhibitor (Pan)
PTEN L182fs Akt Inhibitor (Pan)
PTEN L318fs Akt Inhibitor (Pan)
PTEN R130Q Akt Inhibitor (Pan)
PTEN G127R Akt Inhibitor (Pan)
PTEN K125N Akt Inhibitor (Pan)
PTEN F56C Akt Inhibitor (Pan)
PTEN Y16fs Akt Inhibitor (Pan)
PTEN Q219* Akt Inhibitor (Pan)
PTEN E157G Akt Inhibitor (Pan)
PTEN N63fs Akt Inhibitor (Pan)
PTEN P95L Akt Inhibitor (Pan)
PTEN I122L Akt Inhibitor (Pan)
PTEN K163fs Akt Inhibitor (Pan)
PTEN H93Q Akt Inhibitor (Pan)
PTEN G129E Akt Inhibitor (Pan)
PTEN inact mut Akt Inhibitor (Pan)
PTEN K260fs Akt Inhibitor (Pan)
PTEN V158fs Akt Inhibitor (Pan)
PTEN Y68D Akt Inhibitor (Pan)
PTEN R130G Akt Inhibitor (Pan)
PTEN V290fs Akt Inhibitor (Pan)
PTEN H118fs Akt Inhibitor (Pan)
PTEN G165* Akt Inhibitor (Pan)
PTEN Y174N Akt Inhibitor (Pan)
PTEN E201* Akt Inhibitor (Pan)
PTEN H118P Akt Inhibitor (Pan)
PTEN Y68fs Akt Inhibitor (Pan)
PTEN K254Rfs*42 Akt Inhibitor (Pan)
PTEN F347L Akt Inhibitor (Pan)
PTEN R130L Akt Inhibitor (Pan)
PTEN D92G Akt Inhibitor (Pan)
PTEN Y27N Akt Inhibitor (Pan)
PTEN A126S Akt Inhibitor (Pan)
PTEN L181P Akt Inhibitor (Pan)
PTEN Q171E Akt Inhibitor (Pan)
PTEN K147* Akt Inhibitor (Pan)
PTEN P96Q Akt Inhibitor (Pan)
PTEN D268Gfs*30 Akt Inhibitor (Pan)
PTEN T348I Akt Inhibitor (Pan)
PTEN K254* Akt Inhibitor (Pan)
PTEN G129R Akt Inhibitor (Pan)
PTEN V217D Akt Inhibitor (Pan)
PTEN G293fs Akt Inhibitor (Pan)
PTEN Q110* Akt Inhibitor (Pan)
PTEN L57W Akt Inhibitor (Pan)
PTEN L70fs Akt Inhibitor (Pan)
PTEN L325R Akt Inhibitor (Pan)
PTEN S10N Akt Inhibitor (Pan)
PTEN P95S Akt Inhibitor (Pan)
PTEN D107V Akt Inhibitor (Pan)
PTEN C136F Akt Inhibitor (Pan)
PTEN L23F Akt Inhibitor (Pan)
PTEN C124fs Akt Inhibitor (Pan)
PTEN A121P Akt Inhibitor (Pan)
PTEN K13Q Akt Inhibitor (Pan)
PTEN Q171* Akt Inhibitor (Pan)
PTEN S287* Akt Inhibitor (Pan)
PTEN M134T Akt Inhibitor (Pan)
PTEN Q298* Akt Inhibitor (Pan)
PTEN Y138L Akt Inhibitor (Pan)
PTEN T232A Akt Inhibitor (Pan)
PTEN F341V Akt Inhibitor (Pan)
PTEN K128Q Akt Inhibitor (Pan)
PTEN K260* Akt Inhibitor (Pan)
PTEN A121E Akt Inhibitor (Pan)
PTEN C105F Akt Inhibitor (Pan)
PTEN R130K Akt Inhibitor (Pan)
PTEN L112R Akt Inhibitor (Pan)
PTEN R14G Akt Inhibitor (Pan)
PTEN N276S Akt Inhibitor (Pan)
PTEN G251C Akt Inhibitor (Pan)
PTEN L108R Akt Inhibitor (Pan)
PTEN K66fs Akt Inhibitor (Pan)
PTEN G20E Akt Inhibitor (Pan)
PTEN Y155H Akt Inhibitor (Pan)
PTEN G165R Akt Inhibitor (Pan)
PTEN negative Akt Inhibitor (Pan)
PTEN R233* Akt Inhibitor (Pan)
PTEN H123Y Akt Inhibitor (Pan)
PTEN del Akt Inhibitor (Pan)
PTEN K342* Akt Inhibitor (Pan)
PTEN T131I Akt Inhibitor (Pan)
PTEN T382S Akt Inhibitor (Pan)
PTEN T319fs Akt Inhibitor (Pan)
PTEN L247_P248del Akt Inhibitor (Pan)
PTEN D24Y Akt Inhibitor (Pan)
PTEN M134L Akt Inhibitor (Pan)
PTEN L112P Akt Inhibitor (Pan)
PTEN E284* Akt Inhibitor (Pan)
PTEN G165E Akt Inhibitor (Pan)
PTEN D22E Akt Inhibitor (Pan)
PTEN P248fs Akt Inhibitor (Pan)
PTEN E106* Akt Inhibitor (Pan)
PTEN R335L Akt Inhibitor (Pan)
PTEN Y27fs Akt Inhibitor (Pan)
PTEN A151P Akt Inhibitor (Pan)
PTEN I122fs Akt Inhibitor (Pan)
PTEN D92V Akt Inhibitor (Pan)
PTEN E284fs Akt Inhibitor (Pan)
PTEN V290* Akt Inhibitor (Pan)
PTEN W111fs Akt Inhibitor (Pan)
PTEN M134I Akt Inhibitor (Pan)
PTEN E256* Akt Inhibitor (Pan)
PTEN C124R Akt Inhibitor (Pan)
PTEN L70V Akt Inhibitor (Pan)
PTEN R173C Akt Inhibitor (Pan)
PTEN C136Y Akt Inhibitor (Pan)
PTEN K263* Akt Inhibitor (Pan)
PTEN R335* Akt Inhibitor (Pan)
PTEN K60fs Akt Inhibitor (Pan)
PTEN P38H Akt Inhibitor (Pan)
PTEN E242* Akt Inhibitor (Pan)
PTEN N94I Akt Inhibitor (Pan)
PTEN E235* Akt Inhibitor (Pan)
PTEN C71Y Akt Inhibitor (Pan)
PTEN L152P Akt Inhibitor (Pan)
PTEN R142W Akt Inhibitor (Pan)
PTEN Y68N Akt Inhibitor (Pan)
PTEN A126D Akt Inhibitor (Pan)
PTEN N12T Akt Inhibitor (Pan)
PTEN K125M Akt Inhibitor (Pan)
PTEN Y65* Akt Inhibitor (Pan)
PTEN A72fs Akt Inhibitor (Pan)
PTEN D331Tfs*13 Akt Inhibitor (Pan)
PTEN E7* Akt Inhibitor (Pan)
PTEN G251V Akt Inhibitor (Pan)
PTEN K267fs Akt Inhibitor (Pan)
PTEN C250fs Akt Inhibitor (Pan)
PTEN T131L Akt Inhibitor (Pan)
PTEN S294fs Akt Inhibitor (Pan)
PTEN Y68C Akt Inhibitor (Pan)
PTEN K128_R130del Akt Inhibitor (Pan)
PTEN K13* Akt Inhibitor (Pan)
PTEN T160I Akt Inhibitor (Pan)
PTEN W111* Akt Inhibitor (Pan)
PTEN H61R Akt Inhibitor (Pan)
PTEN S170R Akt Inhibitor (Pan)
PTEN D326N Akt Inhibitor (Pan)
PTEN loss Akt Inhibitor (Pan)
PTEN L325F Akt Inhibitor (Pan)
PTEN N117S Akt Inhibitor (Pan)
PTEN H123D Akt Inhibitor (Pan)
PTEN G165V Akt Inhibitor (Pan)
PTEN C218* Akt Inhibitor (Pan)
PTEN K128T Akt Inhibitor (Pan)
PTEN H93D Akt Inhibitor (Pan)
PTEN T167P Akt Inhibitor (Pan)
PTEN N48K Akt Inhibitor (Pan)
PTEN A126V Akt Inhibitor (Pan)
PTEN A34D Akt Inhibitor (Pan)
PTEN Y176* Akt Inhibitor (Pan)
PTEN Q214* Akt Inhibitor (Pan)
PTEN E299* Akt Inhibitor (Pan)
PTEN N323fs Akt Inhibitor (Pan)
PTEN K102fs Akt Inhibitor (Pan)
PTEN F271S Akt Inhibitor (Pan)
PTEN N184Efs*16 Akt Inhibitor (Pan)
PTEN L345Q Akt Inhibitor (Pan)
PTEN K125E Akt Inhibitor (Pan)
PTEN N292fs Akt Inhibitor (Pan)
PTEN Q17* Akt Inhibitor (Pan)
PTEN D24G Akt Inhibitor (Pan)
PTEN K254fs Akt Inhibitor (Pan)
PTEN D331fs Akt Inhibitor (Pan)
PTEN P246fs Akt Inhibitor (Pan)
PTEN Y155fs Akt Inhibitor (Pan)
PTEN F337fs Akt Inhibitor (Pan)
PTEN L193fs Akt Inhibitor (Pan)
PTEN D107Y Akt Inhibitor (Pan)
PTEN I122S Akt Inhibitor (Pan)
PTEN N323Kfs*2 Akt Inhibitor (Pan)
PTEN F241S Akt Inhibitor (Pan)
PTEN A126P Akt Inhibitor (Pan)
PTEN R173P Akt Inhibitor (Pan)
PTEN V275* Akt Inhibitor (Pan)
PTEN K125* Akt Inhibitor (Pan)
PTEN K322E Akt Inhibitor (Pan)
PTEN T131A Akt Inhibitor (Pan)
PTEN E288fs Akt Inhibitor (Pan)
PTEN V290Sfs*8 Akt Inhibitor (Pan)
PTEN G36E Akt Inhibitor (Pan)
PTEN C124N Akt Inhibitor (Pan)
PTEN T321fs Akt Inhibitor (Pan)
PTEN Y27S Akt Inhibitor (Pan)
PTEN R14fs Akt Inhibitor (Pan)
PTEN I8Dfs*3 Akt Inhibitor (Pan)
PTEN G44D Akt Inhibitor (Pan)
PTEN Y240* Akt Inhibitor (Pan)
PTEN K6E Akt Inhibitor (Pan)
PTEN R15S Akt Inhibitor (Pan)
PTEN E285* Akt Inhibitor (Pan)
PTEN R130* Akt Inhibitor (Pan)
PTEN V255A Akt Inhibitor (Pan)
PTEN A39P Akt Inhibitor (Pan)
PTEN S227F Akt Inhibitor (Pan)
PTEN D252Y Akt Inhibitor (Pan)
PTEN N329fs Akt Inhibitor (Pan)
PTEN A34P Akt Inhibitor (Pan)
PTEN G129* Akt Inhibitor (Pan)
PTEN V217fs Akt Inhibitor (Pan)
PTEN W274fs Akt Inhibitor (Pan)
PTEN L42R Akt Inhibitor (Pan)
PTEN E73K Akt Inhibitor (Pan)
PTEN R173fs Akt Inhibitor (Pan)
PTEN K125L Akt Inhibitor (Pan)
PTEN G36R Akt Inhibitor (Pan)
PTEN R55fs Akt Inhibitor (Pan)
PTEN S385* Akt Inhibitor (Pan)
PTEN H93Y Akt Inhibitor (Pan)
PTEN Y27C Akt Inhibitor (Pan)
PTEN Y68H Akt Inhibitor (Pan)
PTEN I135K Akt Inhibitor (Pan)
PTEN T319del Akt Inhibitor (Pan)
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
HRAS E162K missense unknown HRAS E162K does not lie within any known functional domains of the Hras protein (UniProt.org). E162K has been identified in the scientific literature (PMID: 22932669), but has not been biochemically characterized and therefore, its effect on Hras protein function is unknown (PubMed, Jan 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA act mut breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, breast cancer cell lines harboring activating mutations in PIK3CA had increased sensitivity to MK2206 in cell culture (PMID: 22932669). 22932669