Mutated EPHA2 is a target for combating lymphatic metastasis in intrahepatic cholangiocarcinoma

Abstract

Exploring the genetic aberrations favoring metastasis is important for understanding and developing novel strategies to combat cancer metastasis. It remains lack of effective treatment for the dismal prognosis of intrahepatic cholangiocarcinoma (ICC). Here, we aimed to study genetic alternations during lymph node metastasis of ICC and investigate potential mechanisms and clinical strategy focused on mutations. We performed whole‐exome sequencing and transcriptome sequencing on samples from 30 ICC patients, including lymph node metastases from five of the patients. We identified the alterations of genetic pattern related to lymph node metastases of ICC. EPHA2, a member of the tyrosine kinase family, was found to be frequently mutated in ICC. Correlation analysis indicated that EPHA2 mutations were closely associated with lymph node metastasis of ICC. In vitro and in vivo experiments revealed that EPHA2 mutations could lead to ligand independent phosphorylation of Ser897, and promote lymphatic metastasis of ICC, in which NOTCH1 signaling pathway played an important role. In both in vitro assays and patient‐derived xenografts, an inhibitor of Ser897 phosphorylation effectively suppressed the metastasis of ICC with mutated EPHA2. Our findings demonstrated that EPHA2 mutants may be an attractive therapeutic target for lymphatic metastasis of ICC.

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

“…ALW-II-41-27, a novel EphA2 tyrosine kinase inhibitor 30 , has obvious anti-tumor effects in the many types of cancers 31 – 36 . Previous studies indicate that ALW-II-41-27 suppresses cancers by targeting S879 phosphorylation of EphA2 32 , 34 , 36 . As our results showed that pY772-EphA2 plays a role in NPC growth, we detected whether pY772-EphA2 is a target of ALW-II-41-27.…”

“…Various therapeutic strategies targeting EphA2, such as EphA2 antibody, ligand Ephrin-A1, Ephrin-A1 mimic peptides, and RNA interference, have been developed 41 . It has been reported that EphA2 tyrosine kinase inhibitor, ALW-II-41-27 30 , has obvious anti-tumor effects in the many types of cancers [31][32][33][34][35][36] . As an EphA2 tyrosine kinase inhibitor, whether ALW-II-41-27 suppresses cancers by inhibiting pY772-EphA2 is unclear.…”

“…Collectively, the results demonstrate that Shp2/Erk-1/2 signaling pathway mediates pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. pY772-EphA2 is a target of EphA2 tyrosine kinase inhibitor ALW-II-41-27 in the NPC cells ALW-II-41-27, a novel EphA2 tyrosine kinase inhibitor 30 , has obvious anti-tumor effects in the many types of cancers [31][32][33][34][35][36] . Previous studies indicate that ALW-II-41-27 suppresses cancers by targeting S879 phosphorylation of EphA2 32,34,36 .…”

“…An ATP-competitive EphA2 tyrosine kinase inhibitor, ALW-II-41-27 30 , possesses obvious in vitro and in vivo anti-tumor effects in lung cancer 31 – 33 , melanoma 34 , triple-negative breast cancer 35 , and intrahepatic cholangiocarcinoma 36 . As an EphA2 tyrosine kinase inhibitor, whether ALW-II-41-27 inhibits cancer progression by inhibiting pY772-EphA2 has not been explored.…”

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

“… 4 , 5 , 6 It is the subordinate most extensive hepatic malignancy after hepatocellular carcinoma, accounting for 15%–20% of primary hepatobiliary malignancies, and the overall incidence of CHOL seems to be increasing worldwide. 7 , 8 , 9 , 10 Most patients have advanced-stage disease at presentation, and the majority of patients with CHOL have a dismal prognosis; surgical resection is the preferred treatment option for patients who have early-stage disease, not for those at late or advanced stages because available systemic therapies are of limited effectiveness. 11 , 12 , 13 Therefore, increased understanding of its molecular tumor biology is urgently required.…”