AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
Vasudevan
Krishna M
KM
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Barbie
David A
DA
Davies
Michael A
MA
Rabinovsky
Rosalia
R
McNear
Chontelle J
CJ
Kim
Jessica J
JJ
Hennessy
Bryan T
BT
Tseng
Hsiuyi
H
Pochanard
Panisa
P
Kim
So Young
SY
Dunn
Ian F
IF
Schinzel
Anna C
AC
Sandy
Peter
P
Hoersch
Sebastian
S
Sheng
Qing
Q
Gupta
Piyush B
PB
Boehm
Jesse S
JS
Reiling
Jan H
JH
Silver
Serena
S
Lu
Yiling
Y
Stemke-Hale
Katherine
K
Dutta
Bhaskar
B
Joy
Corwin
C
Sahin
Aysegul A
AA
Gonzalez-Angulo
Ana Maria
AM
Lluch
Ana
A
Rameh
Lucia E
LE
Jacks
Tyler
T
Root
David E
DE
Lander
Eric S
ES
Mills
Gordon B
GB
Hahn
William C
WC
Sellers
William R
WR
Garraway
Levi A
LA
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000235:genetics; D000099184:Serum-Glucocorticoid Regulated Kinases
D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000631429:PDK1 protein, human; C484760:PIK3CA protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases; C494929:PTEN protein, human