Background: Aberrant AKT activation is prevalent across human cancer lineages, providing an important therapeutic target. AKT comprises three isoforms that mediate critical non-redundant, even opposing functions in cancer pathophysiology. Therefore, targeting specific AKT isoforms in particular cancers may be more effective than pan-AKT inhibition while avoiding disadvantages of pan-AKT inhibition. Currently, AKT isoform-specific expression and activation in cancer are not clearly characterized.
Methods: We systematically characterized AKT isoform-specific expression and activation in 211 cancer cell lines derived from different lineages and genetic backgrounds using a reverse-phase protein array platform.
Results: We found that phosphorylation, but not expression, of AKT1 and AKT2 was coordinated in most but not all cells. Different cancer lineages displayed differential AKT1 and AKT2 expression and phosphorylation. A PIK3CA hotspot mutation H1047R but not E545K was associated with selective activation of AKT2 but not AKT1.
Conclusions: Our study identified and validated AKT isoform-specific expression and phosphorylation in certain cell lines and demonstrated that genetic changes can affect AKT isoform-specific activation. These results provide a more precise understanding of AKT isoform-specific signaling and, in addition, facilitate AKT isoform targeting for personalized cancer therapies.
[1]Shandong Univ, Dept Breast & Thyroid Surg, Shandong Prov Hosp, Jinan, Shandong, Peoples R China;
[2]Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, 1515 Holcombe Blvd, Houston, TX 77030 USA;
[3]Univ Texas MD Anderson Canc Ctr, Genitourinaiy Med Oncol, Houston, TX 77030 USA;
[4]Univ Texas MD Anderson Canc Ctr, Inst Personalized Canc Therapy, Houston, TX 77030 USA;
[5]Fudan Univ, Canc Hosp, Dept Intervent Radiol, Shanghai 200032, Peoples R China
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