The EphB2-MYC Axis is a Major Determinant of Barrett's Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer

Venkitachalam, S.; Babu, D.; Ravillah, D.; Katabathula, R. M.; Joseph, P.; Singh, S.; Udhayakumar, B.; Miao, Y.; Martinez-Uribe, O.; Hogue, J. A.; Kresak, A. M.; Dawson, D.; LaFramboise, T.; Willis, J. E.; Chak, A.; Garman, K. S.; Blum, A. E.; Varadan, V.; Guda, K.

doi:10.1101/2021.05.13.444044

bioRxiv · 10.1101/2021.05.13.444044

The EphB2-MYC Axis is a Major Determinant of Barrett's Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer

Venkitachalam, S.·Babu, D.·Ravillah, D.·Katabathula, R. M.·Joseph, P.·Singh, S.·Udhayakumar, B.·Miao, Y.·Martinez-Uribe, O.·Hogue, J. A.·Kresak, A. M.·Dawson, D.·LaFramboise, T.·Willis, J. E.·Chak, A.·Garman, K. S.·Blum, A. E.·Varadan, V.·Guda, K.

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Abstract

Esophageal adenocarcinoma (EAC), a highly aggressive cancer with limited therapeutic options, often arises in the backdrop of a molecularly-complex esophageal metaplasia disorder, Barretts Esophagus (BE). Using transcriptomics and systems biology analyses of treatment-naive malignant/pre-malignant biopsy tissues, we found Eph receptor B2 (EphB2) tyrosine kinase signaling to be frequently hyperactivated during early stages of EAC development, and across the BE-EAC continuum. Functional studies revealed EphB2 to be an upstream post-translational regulator of c-MYC activity and as a key molecular dependency in BE/EAC. Single-cell transcriptomics in a porcine esophageal 3D spheroid model showed enhanced EphB2 and MYC activity to be significantly associated with BE-like cell fate. shRNA-based knockdown of EphB2 or small molecule inhibitors of MEK, that modulate MYC protein stability, proved effective in suppressing EAC tumor growth in vivo. These findings point to EphB2-MYC axis as an early promoter of EAC and a novel therapeutic vulnerability in this increasingly-prevalent esophageal malignancy. STATEMENT OF SIGNIFICANCEWe identify EphB2 signaling as a potential master regulator and early promoter of esophageal adenocarcinoma, and the proto-oncogene MYC as a key downstream effector of EphB2 function. Targeting the EphB2-MYC axis could be a promising therapeutic strategy for these often refractory and lethal EAC tumors.

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Venkitachalam, S., Babu, D., Ravillah, D., Katabathula, R. M., Joseph, P., Singh, S., Udhayakumar, B., Miao, Y., Martinez-Uribe, O., Hogue, J. A., Kresak, A. M., Dawson, D., LaFramboise, T., Willis, J. E., Chak, A., Garman, K. S., Blum, A. E., Varadan, V., Guda, K.. 2021-05-15. The EphB2-MYC Axis is a Major Determinant of Barrett's Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer. https://doi.org/10.1101/2021.05.13.444044

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