Protein and Cell: The Zhejiang University Junxia team reveals the important mechanisms of gastrointestinal tumor targeting drug resistance.

According to the latest world cancer statistics, gastrointestinal cancer not only has a high incidence (about 15.9%) but also has a mortality rate of more than 17.4%.however, the mutation frequency of ERBB3 in gastrointestinal tumors is very high (about 12%), which is much higher than that of lung cancer (2%), breast cancer (2%) and other cancer types.therefore, the role and mechanism of ERBB3 mutation gene in gastrointestinal cancer need to be studied.on July 7, min Junxia team, School of Medicine / Institute of translational medicine, Zhejiang University, published a research paper entitled rewiring ERBB3 and ERK signaling conferences resistance to FGFR1 inhibition in gastric cancer harbored an erbb3-e928g mutation online in protein & amp; cell (impact factor 10.164).in this study, a series of tyrosine kinase inhibitors (tyrosine kinase 3) commonly used in clinical practice of gastrointestinal cancer cell lines carrying ERBB3 (ERBB3 receptor tyrosine kinase 3) mutations were screened It was found that the gastrointestinal cancer cells carrying erbb3-e928g mutation were significantly tolerant to FGFR1 inhibitors; further studies showed that inhibition of ERBB3 (specific antibody ljm716 or sherbb3) could effectively reverse the tolerance of gastrointestinal cancer cells to FGFR1 inhibitors.this study is the first time to clarify the molecular regulatory mechanism of ERBB3 e928g mutation leading to targeted treatment tolerance of gastrointestinal cancer, and provide a new target and new strategy for clinical treatment.ERBB3 gene was discovered in 1989. The same family members include ErbB1 (EGFR), erbB2 (HER2) and ErbB4.since 2004, a number of studies have suggested that abnormal ERBB3 activation is related to the tolerance of tumor targeted therapeutic drugs, such as EGFR and HER2 inhibitors. In 2014, ERBB3 was identified as oncogene.however, the specific regulatory mechanism of how mutant ERBB3 leads to tumor targeted drug tolerance remains unclear.the researchers first analyzed ERBB3 gene and other related tyrosine kinase receptors (ERBB3) in 797 gastrointestinal cancer samples by digging the Cancer Gene Atlas (TCGA) database, The results showed that 9% of the samples had ERBB3 gene changes, and most of them were missense mutations (73.3% of all gene changes).TCGA database was used to analyze the mutation rule of ERBB3 and related RTK genes in gastrointestinal tumor samples. Based on the analysis results of ERBB3 mutation spectrum in patients with gastrointestinal cancer, the researchers selected gastrointestinal cancer cell lines with different high frequency hot spot mutations of ERBB3 to carry out a series of TKIs tolerance function screening. The results showed that the tumor cell lines carrying the e28g mutation ERBB3 had a significant effect on fgfr1-3 Furthermore, the inhibition and tolerance of FGFR1 was confirmed by PD173074 [5] and knockdown of FGFR1 gene expression.ERBB3 cell lines carrying the e928g mutation were resistant to FGFR1 inhibition. In addition, the researchers found that ERBB3 phosphorylation level (perbb3) in the tumor cell lines carrying the e929g mutation ERBB3 was significantly higher than that in other tumor cell lines, suggesting that ERBB3 signal was abnormally activated.then, does FGFR1 inhibit tolerance dependent on abnormally activated ERBB3? On the one hand, the researchers used shRNA to knock down the ERBB3 mutation of e928g in tumor cells, which reduced the protein level of perbb3, and found that it could effectively improve the killing effect of FGFR1 inhibitor on tumor cells; on the other hand, the researchers used a combination of ERBB3 specific antibody ljm716 and FGFR1 inhibitor to treat tumor cells, which could also significantly reduce the tumor cell vitality Inhibition of tumor cell clone formation and induction of tumor cell apoptosis.in order to clarify the related mechanism, the researchers systematically studied the downstream signal pathway of abnormal activation of ERBB3. The results showed that the protein level of phosphorylated ERK (perk) in tumor cells with mutation ERBB3 at e929g site was significantly higher than that in other tumor cell lines, and the combined inhibition of mutation ERBB3 and FGFR1 could significantly down regulate the level of perk, suggesting that abnormal activation of ERK signal is involved in the regulation of e928g process ERBB3 tumor cells were resistant to FGFR1 inhibitors.ERBB3 protein has no kinase activity in the intracellular kinase region, which is a kind of "false kinase", which leads to the formation of heterodimer with other RTKs in order to activate the downstream intracellular signal pathway proteins.some studies have found that ERBB3 often forms heterodimer with HER2 or EGFR in tumor cells, and can also form heterodimer with other RTK family members, such as igf1-r and c-Met.therefore, further studies have found that the e928g mutant ERBB3, rather than the wild-type ERBB3, does interact with FGFR1, suggesting that ERBB3 with e928g mutation can activate downstream ERK signaling pathway by forming heterodimer with FGFR1, thus promoting tumor cell survival and drug resistance. is this study promising for clinical transformation? In order to answer this key scientific question, the researchers conducted a series of in vivo animal studies by using tumor bearing mouse models. The results showed that the combination of ERBB3 and FGFR1 could significantly inhibit the growth of tumor in mice, which provided an important basis for the clinical transformation of the results. in combination with targeted inhibition of ERBB3 and FGFR1 in tumor bearing mice, the research results showed that gastrointestinal cancer cells carrying e28g hot spot mutation ERBB3 were significantly tolerant to FGFR1 inhibitors through systemic TKIs tolerance screening. The potential mechanism is that e28g mutant ERBB3 and FGFR1 form heterodimer, abnormally activate ERBB3 and downstream ERK signaling pathways, and promote tumor cell survival and tolerance Medicine. the research results provide a solid experimental basis and new strategy for the clinical treatment of gastrointestinal cancer with targeted mutation ERBB3 and FGFR1. research findings and important mechanism model diagram it is reported that Yang Xiang and Wang Hongxiao, doctoral students of Professor Min Junxia's team from Medical College of Zhejiang University / Institute of translational medicine, are the co first authors, and Professor Min Junxia is the corresponding author. the research team of Zhejiang University of medicine strongly supported. the research was supported by the natural science foundation of Zhejiang Province, the national key R & D program and the National Natural Science Foundation of China. the first author and corresponding author of the paper (front left: Yang Xiang, middle row: Wang Hongxiao, front row right: Professor Min Junxia)