Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition.
Specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We used a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth inhibition by small-molecule MEK inhibitors. Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in response to MEK inhibition through a negative MEK-epidermal growth factor receptor-PI3K feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3K produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.
Mirzoeva
Olga K
OK
Department of Medicine, Division of Gastroenterology, University of California, San Francisco, California 94115, USA.
Das
Debopriya
D
Heiser
Laura M
LM
Bhattacharya
Sanchita
S
Siwak
Doris
D
Gendelman
Rina
R
Bayani
Nora
N
Wang
Nicholas J
NJ
Neve
Richard M
RM
Guan
Yinghui
Y
Hu
Zhi
Z
Knight
Zachary
Z
Feiler
Heidi S
HS
Gascard
Philippe
P
Parvin
Bahram
B
Spellman
Paul T
PT
Shokat
Kevan M
KM
Wyrobek
Andrew J
AJ
Bissell
Mina J
MJ
McCormick
Frank
F
Kuo
Wen-Lin
WL
Mills
Gordon B
GB
Gray
Joe W
JW
Korn
W Michael
WM
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D002166:Camptothecin; D019938:Cyclin D1; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors