First Axl inhibitor enters clinical trials (original) (raw)

Axl and Mer are both members of the TAM receptor family, which also includes Tyro3, a kinase that is particularly abundant in the brain. All three are activated by a common ligand, Growth Arrest–specific protein 6 (Gas6), and they ordinarily play an embryonic developmental role in cell survival, migration and differentiation. High levels of Axl expression have been correlated with poor survival in many types of cancer, including breast cancer (Proc. Natl. Acad. Sci. USA 107, 1124–1129, 2010), acute myeloid leukemia (Amer. Soc. Hematol. Annual Meeting, San Diego 2011), glioblastoma multiforme (Clin. Cancer Res. 14, 130–138, 2008) and osteosarcoma (Biochem. Biophys. Res. Commun. 435, 493–500, 2013). In addition, activation of Axl kinase has been identified as one mechanism by which lung cancers can develop resistance to therapies targeting EGFR, such as Tarceva (erlotinib) (Nat. Genet. 44, 852–60, 2012).

BergenBio, of Bergen, Norway, gained a position in this area in 2011 by in-licensing BGB324 (formerly R428) from S. San Francisco, California–based Rigel Pharmaceuticals. BergenBio's co-founder and CSO Jim Lorens, who is also based at the University of Bergen, was previously at Rigel. His research has demonstrated that an epithelial-to-mesenchymal transition (EMT)—a developmental process that can be exploited by tumor cells—upregulates Axl kinase expression in breast cancer, and that this is an essential step for cancer metastasis and progression. “It makes the cells very resistant to a hostile microenvironment,” says BergenBio's CEO, Richard Godfrey. Moreover, Axl kinase and Gas6 then form a positive-feedback loop, which maintains the mesenchymal phenotype. An additional, emerging line of evidence suggests that the EMT process may also stimulate the formation of cancer stem cells, although Godfrey notes the cancer stem cell concept remains controversial. “They're certainly cancer-seeding or cancer-propagating cells,” he says.

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