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|Ref Type||Journal Article|
|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|
|Date||2012 Oct 15|
|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.|
|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|
|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, Jun 2020).|
|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|