Abstract
Mutations in K-Ras and epidermal growth factor receptor (EGFR) are mutually exclusive, but it is not known how K-Ras activation inactivates EGFR, leading to resistance of cancer cells to anti-EGFR therapy. Here, we report that the K-Ras effector p38γ MAPK confers intrinsic resistance to small molecular tyrosine kinase inhibitors (TKIs) by concurrently stimulating EGFR gene transcription and protein dephosphorylation. We found that p38γ increases EGFR transcription by c-Jun-mediated promoter binding and stimulates EGFR dephosphorylation via activation of protein-tyrosine phosphatase H1 (PTPH1). Silencing the p38γ/c-Jun/PTPH1 signaling network increased sensitivities to TKIs in K-Ras mutant cells in which EGFR knockdown inhibited growth. Similar results were obtained with the p38γ-specific pharmacological inhibitor pirfenidone. These results indicate that in K-Ras mutant cancers, EGFR activity is regulated by the p38γ/c-Jun/PTPH1 signaling network, whose disruption may be a novel strategy to restore the sensitivity to TKIs.
Highlights
Mutations in K-Ras and epidermal growth factor receptor (EGFR) are mutually exclusive, but it is not known how K-Ras activation inactivates EGFR, leading to resistance of cancer cells to anti-EGFR therapy
We found that p38␥ increases EGFR transcription by c-Jun-mediated promoter binding and stimulates EGFR dephosphorylation via activation of protein-tyrosine phosphatase H1 (PTPH1)
To determine whether K-Ras mutation causes the unresponsiveness to tyrosine kinase inhibitors (TKIs) as observed clinically [7], colon cancer cells with and without mutated K-Ras were analyzed for growth inhibition by the Food and Drug Administration-approved TKIs lapatinib (Lap) and gefitinib (Gef)
Summary
The K-Ras effector p38␥ MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation. Ning Yin‡1, Adrienne Lepp‡1, Yongsheng Ji‡1, Matthew Mortensen‡, Songwang Hou‡, Xiao-Mei Qi‡, Charles R. Myers‡, and Guan Chen‡§2 From the ‡Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and the §Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295
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