Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism.

Discovery of MINC1, a GTPase-activating protein small molecule inhibitor, targeting MgcRacGAP.

The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers.

Tools to study the function of the Ras-related, estrogen-regulated growth inhibitor in breast cancer.

The Ras-related, estrogen-regulated growth inhibitor (Rerg) is a Ras-related small GTPase and candidate tumor suppressor. Rerg gene expression is stimulated by the estrogen receptor alpha (ERalpha), and Rerg gene expression is absent in ER-negative breast cancers. ER-negative breast cancers are highly invasive and metastastic and are typically more advanced than their ER-positive counterparts.

Ras-mediated intestinal epithelial cell transformation requires cyclooxygenase-2-induced prostaglandin E2 signaling.

Ras-mediated transformation is associated with upregulation of cyclooxygenase-2 (COX-2), which in turn promotes prostaglandin E2 (PGE2) synthesis and secretion. Although recent studies have identified molecular mechanisms by which Ras mediates upregulation of COX-2, conflicting observations have been made. Furthermore, while COX-2 upregulation has been shown to be important for Ras transformation, the signaling pathways initiated by PGE2-stimulation of EP family of heterotrimeric G protein-coupled receptors (GPCR) and contribution of PGE2 signaling to Ras-mediated transformation are issues that remain unresolved.

Characterization of RERG: an estrogen-regulated tumor suppressor gene.

RERG (Ras-related and estrogen-regulated growth inhibitor), a gene that encodes a small GTP binding and hydrolyzing protein (GTPase) of the Ras superfamily, was originally identified in gene microarray analysis as a gene of which expression is down-regulated in estrogen receptor (ER)-negative breast tumors. Subsequently, RERG mRNA was detected in ER-positive breast tumor-derived cell lines, but not in any of the ER-negative cell lines examined. Furthermore, a comparison of matched tumor and normal tissue samples suggests that RERG expression is lost in kidney, breast, ovary, and colon tumors.

Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?

Ras proteins function as signal transducers and are mutationally activated in many human cancers. In 1993, Raf was identified as a key downstream effector of Ras signaling, and it was believed then that the primary function of Ras was simply to facilitate Raf activation. However, the subsequent discovery of other proteins that are effectors of Ras function suggested that oncogenic activities of Ras are mediated by both Raf-dependent and Raf-independent signaling.

Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis.

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation.