Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma

Abstract

Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

“…Colorectal cancer (CRC) is the second most occurring neoplasia in men and the third in women, and the second leading cause of cancer-related deaths worldwide. Solid epidemiologic data show that in 2018 there were over 1.8 million new cases [ 1 ], raising a significant scientific interest [ 2 , 3 , 4 , 5 , 6 ]. Unfortunately, about 30–40% of patients have at diagnosis a metastatic CRC (mCRC), and an additional 30% will develop it later.…”

Improving prediction performance of colon cancer prognosis based on the integration of clinical and multi-omics data

“…These included PRSS2, EPHB6 and FABP4, which showed correlation with colorectal cancer prognosis, whereas high expression of these genes was related to poor prognosis [41][42][43]. These genes were enriched in Reactome pathway EPH-ephrin mediated repulsion of cells, which might be a potential therapeutic target in colon cancer [44,45].…”

The EPH/Ephrin System in Colorectal Cancer

“…The importance of the EPHB-triggered signaling cascade to support the proliferation of CRC cells has been extensively documented. NVP-Iso, an EPH-specific tyrosine kinase inhibitor (TKI), causes tumor growth retardation on mice models, inducing an autophagy-mediated cell death [ 72 ]. The major advantages from the utilization of those agents could be derived by the elective signaling blockage of the EPH tyrosine kinase family, which could significantly limit their side-effects profile.…”