Oncogenic K-ras activates p38 to maintain colorectal cancer cell proliferation during MEK inhibition.
BACKGROUND
Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling.


METHODS
K-ras mutant colorectal tumor cell lines C26, HCT116 and L169 were used. K-ras or components of the MEK/ERK and p38 pathway were suppressed by RNA interference (RNAi). MEK was inhibited by U0126. p38 was inhibited by SB203850.


RESULTS
MEK inhibition, or suppression of MEK1/2 or ERK1/2 by RNA interference, reduced the proliferation rate of all colorectal cancer cell lines. However, cell proliferation returned to normal after two weeks of chronic inhibition, despite the continued suppression of MEK or ERK. In contrast, K-ras-suppressed tumor cells entered an irreversible senescent-like state following ERK pathway inhibition. MEK inhibition or ERK1/2 suppression caused activation of p38alpha in a K-ras-dependent manner. Inhibition or suppression of p38alpha prevented the recovery of K-ras mutant tumor cells during prolonged MEK inhibition.


CONCLUSIONS
Oncogenic K-ras activates p38alpha to maintain cell proliferation during MEK inhibition. MEK-targeting therapeutics can create an acquired tumor cell dependency on p38alpha.
van Houdt
Winan J
WJ
Department of Surgery, University Medical Center Utrecht, Heidelberglaan, Utrecht, The Netherlands.
de Bruijn
Menno T
MT
Emmink
Benjamin L
BL
Raats
Danielle
D
Hoogwater
Frederik J H
FJ
Borel Rinkes
Inne H M
IH
Kranenburg
Onno
O
D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006131:Growth Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D002070:Butadienes; D006131:Growth Inhibitors; C000715470:MAS1 protein, human; D009570:Nitriles; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases