Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions.
The phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway regulates a broad spectrum of physiologic and pathologic processes. In breast cancer mutation, amplification, deletion, methylation, and posttranslational modifications lead to significant dysregulation of this pathway leading to more aggressive and potentially drug-resistant disease. Multiple novel agents, targeting different nodes within the pathway are currently under development by both commercial and academic partners. The key to the successful validation of these markers is selection of the appropriate patient groups using biomarkers. This article reviews current progress in this area, highlighting the key molecular alterations described in genes within the PI3K/Akt/mTOR pathway that may have an effect on response to current and future therapeutic interventions. Herein, gaps in current knowledge are highlighted and suggestions for future research directions given that may facilitate biomarker development in partnership with current drug development.
Endocrine Cancer Group and Edinburgh Breakthrough Breast Cancer Laboratory, Edinburgh University,Western General Hospital, Crewe Road South, Edinburgh, UK. john.bartlett@ed.ac.uk
John M S
JM
Bartlett
D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005544:Forecasting; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000235:genetics; D018579:Patient Selection; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human