Résumé
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the Western world. Cancer that metastasizes to distant sites is usually not curable, although chemotherapy can extend survival. Recently, a novel immunotherapy approach based on targeting of the tyrosine kinase (TK) EGFR was shown to significantly improve the survival of patients with metastatic CRC (mCRC). However, only patients with a wild-type KRAS may hope respond to EGFR inhibition. The majority of patients expresses oncogenic components of Ras signaling and thus have hyperactive Ras cascade operating independently from EGFR. Therefore, there is an urgent need to discover new Ras-independent oncogenic targets that regulate tumor cell invasion and metastasis in patients with mCRC. Using a pharmacological screen, we uncovered an additional TK that regulates CRC cell invasion and metastasis induction irrespective of KRAS mutation. Specifically, the clinically available TK inhibitor nilotinib (Tasigna) originally developed to target imatinib-resistant Bcr-Abl alleles in leukemia, also inhibits invasive properties of CRC cells. Nilotinib also strongly reduces liver metastases that were induced after injection of mCRC cells in the spleen of nude mice. Remarkably, the potency of nilotinib to inhibit invasive activity of mCRC cells was similar to the one observed in leukemia. 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 the highest affinity target of nilotinib (Rix et al, Blood, 110:4055-63). DDR1 is a poorly-characterized TK and a receptor for collagen, the major component of the extracellular matrix. We found that DDR1 is overexpressed in CRC and regulates CRC cell-induced invasion in vitro and liver metastasis formation in vivo. Finally, we have obtained evidence supporting that the pharmacological activity of nilotinib in CRC cells is mediated by inhibition of DDR1. Indeed, introduction of the nilotinib resistant DDR1 T701I mutant into CRC cells renders these cells resistant to nilotinib. Overall, our data suggest that targeting DDR1 by nilotinib may be a therapeutic value in patients with mCRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 855. doi:1538-7445.AM2012-855