EPHA2 and WNT reciprocally regulate MAPK-dependent gene expression in a pancreatic cancer model
4 affiliations
- 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
- 2Cancer Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
- 3Wenzhou Medical University-Monash BDI Alliance in Clinical and Experimental Biomedicine, Wenzhou Medical University, Wenzhou, China.
- 4Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
Abstract
Wnt signaling drives tumorigenesis in multiple cancers, in part through complex interactions with other oncogenic pathways including the MAPK cascade. In Wnt-addicted cancers, pharmacological and genetic inhibition of Wnt signaling activates multiple RTKs, increases ERK phosphorylation, and induces MAPK target gene expression, but the specific RTKs responsible for this MAPK hyperactivation are not known. Here, we performed phosphotyrosine-targeted mass spectrometry, which revealed robust phosphorylation of EPHA2 and EGFR upon Wnt inhibition. Unexpectedly, we found that in xenografts, EPHA2 suppresses EGFR and ERK activation. Most notably, the increased ERK phosphorylation observed in EPHA2-KO tumors is transcriptionally inert, as there is no concomitant increase in MAPK target gene expression until concomitant Wnt inhibition. This suggests a Wnt-activated transcriptional repressor such as GATA3 that gates MAPK signaling in Wnt-high cancers. Although Wnt-high KRAS-mutant cancers are resistant to erlotinib alone, adding a Wnt inhibitor mitigates this resistance. Additionally, loss of EPHA2 enhances these cancers’ sensitivity to both erlotinib and Wnt inhibitors. Our studies therefore identify therapeutic vulnerabilities in Wnt-high tumors, even within traditionally EGFR inhibitor-resistant, RAS-mutant contexts.
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BibTeX
@article{wadia2026epha2,
title = {{EPHA2 and WNT reciprocally regulate MAPK-dependent gene expression in a pancreatic cancer model}},
author = {Shawn R. Wadia and Changyuan Hu and Siddhi Patnaik and Shreya Sridharan and Roger J. Daly and David M. Virshup and Babita Madan},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.202630},
url = {https://doi.org/10.1172/jci.insight.202630},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - EPHA2 and WNT reciprocally regulate MAPK-dependent gene expression in a pancreatic cancer model
AU - Shawn R. Wadia
AU - Changyuan Hu
AU - Siddhi Patnaik
AU - Shreya Sridharan
AU - Roger J. Daly
AU - David M. Virshup
AU - Babita Madan
PY - 2026
DA - 2026/09/08
JO - JCI Insight
DO - 10.1172/jci.insight.202630
UR - https://doi.org/10.1172/jci.insight.202630
AB - Wnt signaling drives tumorigenesis in multiple cancers, in part through complex interactions with other oncogenic pathways including the MAPK cascade. In Wnt-addicted cancers, pharmacological and genetic inhibition of Wnt signaling activates multiple RTKs, increases ERK phosphorylation, and induces MAPK target gene expression, but the specific RTKs responsible for this MAPK hyperactivation are not known. Here, we performed phosphotyrosine-targeted mass spectrometry, which revealed robust phosphorylation of EPHA2 and EGFR upon Wnt inhibition. Unexpectedly, we found that in xenografts, EPHA2 suppresses EGFR and ERK activation. Most notably, the increased ERK phosphorylation observed in EPHA2-KO tumors is transcriptionally inert, as there is no concomitant increase in MAPK target gene expression until concomitant Wnt inhibition. This suggests a Wnt-activated transcriptional repressor such as GATA3 that gates MAPK signaling in Wnt-high cancers. Although Wnt-high KRAS-mutant cancers are resistant to erlotinib alone, adding a Wnt inhibitor mitigates this resistance. Additionally, loss of EPHA2 enhances these cancers’ sensitivity to both erlotinib and Wnt inhibitors. Our studies therefore identify therapeutic vulnerabilities in Wnt-high tumors, even within traditionally EGFR inhibitor-resistant, RAS-mutant contexts.
SN - 2379-3708
ER -