YES1

Abstract: Targeting genetic alterations of oncogenes by molecular-targeted agents (MTA) is an effective approach for treating cancer. However, there are still no clinical MTA options for many cancers, including esophageal cancer. We used a short hairpin RNA library to screen for a new oncogene in the esophageal cancer cell line KYSE70 and identified YES proto-oncogene 1 (YES1) as having a significant impact on tumor growth. An analysis of clinical samples showed that YES1 gene amplification existed not only in esophageal cancer but also in lung, head and neck, bladder, and other cancers, indicating that YES1 would be an attractive target for a cancer drug. Because there is no effective YES1 inhibitor so far, we generated a YES1 kinase inhibitor, CH6953755. YES1 kinase inhibition by CH6953755 led to antitumor activity against YES1-amplified cancers in vitro and in vivo. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1-amplified cancers. YES1 regulated YAP1 transcription activity by controlling its nuclear translocation and serine phosphorylation. These findings indicate that the regulation of YAP1 by YES1 plays an important role in YES1-amplified cancers and that CH6953755 has therapeutic potential in such cancers. SIGNIFICANCE: These findings identify the SRC family kinase YES1 as a targetable oncogene in esophageal cancer and describe a new inhibitor for YES1 that has potential for clinical utility.See related commentary by Rai, p. 5702.

Abstract: Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2-YES1-ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2-YES1-ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

Abstract: Normal cellular behavior can be described as a complex, regulated network of interaction between genes and proteins. Targeted cancer therapies aim to neutralize specific proteins that are necessary for the cancer cell to remain viable in vivo. Ideally, the proteins targeted should be such that their downregulation has a major impact on the survival/fitness of the tumor cells and, at the same time, has a smaller effect on normal cells. It is difficult to use standard analysis methods on gene or protein expression levels to identify these targets because the level thresholds for tumorigenic behavior are different for different genes/proteins. We have developed a novel methodology to identify therapeutic targets by using a new paradigm called “gene centrality.” The main idea is that, in addition to being overexpressed, good therapeutic targets should have a high degree of connectivity in the tumor network because one expects that suppression of its expression would affect many other genes. We propose a mathematical quantity called “centrality,” which measures the degree of connectivity of genes in a network in which each edge is weighted by the expression level of the target gene. Using our method, we found that several SRC proto-oncogenes LYN, YES1, HCK, FYN, and LCK have high centrality in identifiable subsets of basal-like and HER2+ breast cancers. To experimentally validate the clinical value of this finding, we evaluated the effect of YES1 knockdown in basal-like breast cancer cell lines that overexpress this gene. We found that YES1 downregulation has a significant effect on the survival of these cell lines. Our results identify YES1 as a target for therapeutics in a subset of basal-like breast cancers.