MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.

Abstract

BACKGROUND:

Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor.

METHODS:

We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer.

RESULTS:

EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer.

CONCLUSIONS:

These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.

• Authors: Yutuan Wu, Jie Huang, Cristina Ivan, Yunjie Sun, Shaolin Ma, Lingegowda S Mangala, Bryan M Fellman, Diana L Urbauer, Nicholas B Jennings, Prahlad Ram, Robert L Coleman, Wei Hu, Anil K Sood
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 163 Issue 1 Pg. 181-190 (10 2021) ISSN: 1095-6859 [Electronic] United States
• PMID: 34391578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Pyridones
• Pyrimidinones
• trametinib
• Receptor, EphA2
• Mitogen-Activated Protein Kinase Kinases
• Dasatinib

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Dasatinib (administration & dosage, therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Humans
• MAP Kinase Signaling System (physiology)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Pyridones (administration & dosage, therapeutic use)
• Pyrimidinones (administration & dosage, therapeutic use)
• Receptor, EphA2 (antagonists & inhibitors, physiology)
• Uterine Neoplasms (drug therapy)