R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.
Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.
Rigel, Inc., 1180 Veteran's Boulevard, South San Francisco, CA 94112, USA. sholland@rigel.com
Sacha J
SJ
Holland
Alison
A
Pan
Christian
C
Franci
Yuanming
Y
Hu
Betty
B
Chang
Weiqun
W
Li
Matt
M
Duan
Allan
A
Torneros
Jiaxin
J
Yu
Thilo J
TJ
Heckrodt
Jing
J
Zhang
Pingyu
P
Ding
Ayodele
A
Apatira
Joanne
J
Chua
Ralf
R
Brandt
Polly
P
Pine
Dane
D
Goff
Rajinder
R
Singh
Donald G
DG
Payan
Yasumichi
Y
Hitoshi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001567:Benzocycloheptenes / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D002277:Carcinoma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
D000970:Antineoplastic Agents; D001567:Benzocycloheptenes; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D014230:Triazoles; C548378:bemcentinib; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase