Anti-ARHGEF5 (internal region) polyclonal antibody

In up to 30% of non-small cell lung cancer (NSCLC) patients, the oncogenic driver of tumor growth is a constitutively activated epidermal growth factor receptor (EGFR). Although these patients gain great benefit from treatment with EGFR tyrosine kinase inhibitors, the development of resistance is inevitable. To model the emergence of drug resistance, an EGFR-driven, patient-derived xenograft (PDX) NSCLC model was treated continuously with Gefitinib in vivo. Over a period of more than three months, three separate clones developed and were subsequently analyzed: Whole exome sequencing and reverse phase protein arrays (RPPAs) were performed to identify the mechanism of resistance. In total, 13 genes were identified, which were mutated in all three resistant lines. Amongst them the mutations in NOMO2, ARHGEF5 and SMTNL2 were predicted as deleterious. The 53 mutated genes specific for at least two of the resistant lines were mainly involved in cell cycle activities or the Fanconi anemia pathway. On a protein level, total EGFR, total Axl, phospho-NF KB, and phospho-Stat1 were upregulated. Stat1, Stat3, MEK1/2, and NF KB displayed enhanced activation in the resistant clones determined by the phosphorylated vs. total protein ratio. In summary, we developed an NSCLC PDX line modelling possible escape mechanism under EGFR treatment. We identified three genes that have not been described before to be involved in an acquired EGFR resistance. Further functional studies are needed to decipher the underlying pathway regulation.

Dbl (B-cell lymphoma)-related guanine nucleotide exchange factors (GEFs), the largest family of GEFs, are directly responsible for the activation of Rho family GTPases and essential for a number of cellular events such as proliferation, differentiation and movement. The members of the Ephexin (Eph-interacting exchange protein) family, a subgroup of Dbl GEFs, initially were named for their interaction with Eph receptors and sequence homology with Ephexin1. Although the first Ephexin was identified about two decades ago, their functions in physiological and pathological contexts and regulatory mechanisms remained elusive until recently. Ephexins are now considered as GEFs that can activate Rho GTPases such as RhoA, Rac, Cdc42, and RhoG. Moreover, Ephexins have been shown to have pivotal roles in neural development, tumorigenesis, and efferocytosis. In this review, we discuss the known and proposed functions of Ephexins in physiological and pathological contexts, as well as their regulatory mechanisms.