IL-1α-Dependent STAT3 Activation Mediates Resistance to MEK Inhibition in Pancreatic Cancer
Abstract
OBJECTIVE: IL-1α is a pro-inflammatory cytokine which has been recently implicated in pancreatic cancer. We identify its novel role in regulating STAT3 activation in response to MEK inhibition. METHODS: A cytokine array was... [ view full abstract ]
OBJECTIVE: IL-1α is a pro-inflammatory cytokine which has been recently implicated in pancreatic cancer. We identify its novel role in regulating STAT3 activation in response to MEK inhibition.
METHODS: A cytokine array was performed on pancreatic tumors treated with MEK inhibitor, identifying down-regulation of IL-1α. To elicit the effects of IL-1α on pancreatic cancer signal transduction, we performed an in vitro kinase array and Western blot analysis on cells stimulated with recombinant IL-1α with and without MEK inhibitor treatment. Tumor xenografts and genetically engineered pancreatic cancer-bearing mice were treated with MEK and STAT3 inhibitors in order to explore the effect of blocking both MEK and STAT3 signaling pathways.
RESULTS: MEK inhibition reduced IL-1α protein and RNA transcript levels and induced activating phosphorylation of STAT3. IL-1α induced inhibitory phosphorylation of STAT3 at an alternate site. Concomitant treatment of pancreatic cancer cells with both MEK inhibitor and IL-1α successfully suppressed MEK signaling while also blocking STAT3 reactivation. Combined MEK and STAT3 blockade suppressed growth of tumor xenografts and increased overall survival in the PKT genetically engineered mouse model.
CONCLUSION: MEK inhibitors are ineffective in Kras-mutant pancreatic cancer due to reciprocal reactivation of STAT3 signaling. This is mediated by secondary loss of IL-1α, which suppresses STAT3 signaling. Our data suggests that combined blockade of both MEK and STAT3 may provide a durable therapy against pancreatic cancer.
Authors
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Alexander Gaidarski
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Casey Roberts
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Michael VanSaun
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Nagaraj Nagathihalli
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Jason Castellanos
(Vanderbilt University Medical Center)
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Nipun Merchant
(University of Miami Leonard M. Miller School of Medicine, Miami, Florida, U.S.A.)
Topic Area
Surgical Oncology
Session
QS-SurgOnc » Quick-Shot Presentations: Surgical Oncology (15:00 - Thursday, 21st September, Lee 404)