Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma

Abstract

Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However, YAP1 is rarely mutated in human ERMS. Instead, the most common mutations in ERMS are oncogenic RAS mutations. First, to compare YAP1 S127A and KRAS G12V-driven rhabdomyosarcomas, we re-analysed gene expression microarray datasets from mouse rhabdomyosarcomas caused by these genes. This revealed that only 20% of the up or downregulated genes are identical, suggesting substantial differences in gene expression between YAP and KRAS-driven rhabdomyosarcomas. As oncogenic RAS has been linked to YAP in other types of cancer, we also tested whether KRAS G12V alone or in combination with loss of p53 and p16 activates YAP in myoblasts. We found that neither KRAS G12V alone nor KRAS G12V combined with loss of p53 and p16 activated Yap or Yap/Taz-Tead1–4 transcriptional activity in C2C12 myoblasts or U57810 cells. In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of KRAS G12V expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between KRAS G12V and YAP1 S127A-driven tumours.

Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells

“…Both drugs inhibit ERBB1/2/4 but only neratinib inhibits Ste20 family kinases [12]. The Ste20 family kinases play key roles in maintaining plasma membrane and Golgi integrity, including cell-cell junctions and maintaining the apical brush border in the GI [13][14][15][16][17][18]. This is of note because the dose-limiting toxicity of neratinib is Grade 3 diarrhea and the drug must be combined with anti-diarrhea medication to reduce this negative sequela in patients; in comparison, the negative GI sequalae of afatinib are lower [19].…”

“…With respect to neratinib, YAP can mediate resistance to drugs such as the B-RAF inhibitor vemurafenib or the MEK1/2/5 inhibitor trametinib that target mutant K-RAS signaling [46]. In myoblasts expressing a mutant K-RAS, YAP cooperates to enhance proliferation and prevent death in vitro and in vivo [47].…”

“…For the kinases neratinib was claimed to inhibit at sub-10 nM concentrations the following information has been published: MST3/4 control the apical brush border of epithelial cells; the major dose limiting toxicity of neratinib is diarrhea, arguing that neratinib is acting in an on-target MST3/4-dependent fashion to cause this event. MST3/4 also coordinate the phosphorylation of cytoskeletal proteins such as Ezrin / Radixin / Moesin (ERM) family to regulate plasma membrane ruffling [13,14]. MAP4K5 is an apical kinase that interacts with GTP binding proteins downstream of G Protein Coupled Receptors, and links GPCR signaling into MAPK pathways [15].…”

Metabolic landscapes in sarcomas

“…Transcriptional profiling of the tumors revealed that YAP1 induces pro-oncogenic effector genes and represses terminal differentiation of myoblasts. In line with these observations, an independent study found no evidence that mutant RAS isoforms were responsible for YAP overexpression in myoblasts [116]. In ARMS, the translocation product PAX3-FOXO1 suppresses HIPPO signaling through overexpression of RASSF4, which inhibits the MST1 kinase.…”

“…In transgenic models, altering HIPPO effectors alone or in combination with other deficits augmented STS frequency [41]. An increased YAP/TAZ nuclear staining is predictive of poor survival in UPS, DDLPS and ERMS [42][43][44][45]116]. Two studies investigated how fusion gene products mediate sarcomagenesis through alteration of the HIPPO pathway in mice.…”