The K-Ras effector p38p38{gamma}MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR de-phosphorylation [Cell Biology]

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 p38γMAPK confers intrinsic resistance to small molecular tyrosine kinase inhibitors (TKIs) by concurrently stimulating EGFR gene transcription and protein de-phosphorylation. We found that p38γ increases EGFR transcription by c-Jun mediated promoter-binding and stimulates EGFR de-phosphorylation 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.

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