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.
Authors
Shawn R. Wadia, Changyuan Hu, Siddhi Patnaik, Shreya Sridharan, Roger J. Daly, David M. Virshup, Babita Madan
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