Résumé
Tyrosine kinases (TK) are frequently deregulated in human cancer and they play important roles in tumor progression. Since then, they have become valuable therapeutic targets and several inhibitors are currently used in the clinic. For example, the BCR-ABL inhibitor nilotinib is currently used for the treatment of patients with chronic myeloid leukemia (CML). Here we show that this antileukemic drug also inhibits invasive properties of colorectal cancer (CRC) cells. Inhibition was observed at the same dose-range for growth inhibition of CML cells. Nilotinib also strongly reduced liver metastasis induced by injection of CRC cells in the spleen of nude mice. Since we could not detect Abl deregulation in CRC cells, we speculated the involvement of an alternative target to be identified. Interestingly, a previous chemical-proteomic approach identified DDR1 as a novel target of nilotinib (Rix et al, Blood, 2007). DDR1 is a poorly-characterized TK and a receptor for collagen, a major component of the extracellular matrix. Accordingly, we found that DDR1 catalytic activity regulates cell invasion and metastasis of CRC cells. In addition, we demonstrate that nilotinib pharmacological activity is mediated by the inhibition of DDR1 in CRC cells: expression of the nilotinib resistant DDR1/T701I mutant renders CRC cells resistant to nilotinib treatment. Finally, we found that DDR1 catalytic activity is significantly increased in metastatic nodules compared to the primary tumor and the healthy tissue of the same patient. Altogether, these data suggest that the targeting of DDR1 by nilotinib may be of therapeutic value in metastatic CRC.
Citation Format: Priscillia Tosti, Cédric Leroy, Valérie Simon, Bruno Robert, Josiane Pierre, Audrey Sirvent, Serge Roche. The antileukemic drug nilotinib inhibits the invasive activity and the metastatic potential of colorectal cancer cells by targeting the receptor tyrosine kinase DDR1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2085. doi:10.1158/1538-7445.AM2013-2085
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.