PT  - JOURNAL ARTICLE
AU  - Frank Hilberg
AU  - Ulrike Tontsch-Grunt
AU  - Anke Baum
AU  - Anh T Le
AU  - Robert C Doebele
AU  - Simone Lieb
AU  - Davide Dianni
AU  - Tilman Voss
AU  - Pilar Garin-Chesa
AU  - Christian Haslinger
AU  - Norbert Kraut
TI  - The triple angiokinase inhibitor nintedanib directly inhibits tumor cell growth and induces tumor shrinkage via blocking oncogenic receptor tyrosine kinases
AID  - 10.1124/jpet.117.244129
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.117.244129
4099  - http://jpet.aspetjournals.org/content/early/2017/12/20/jpet.117.244129.short
4100  - http://jpet.aspetjournals.org/content/early/2017/12/20/jpet.117.244129.full
AB  - The triple angiokinase inhibitor nintedanib is an orally available, potent and selective inhibitor of tumor angiogenesis by blocking the tyrosine kinase activities of VEGFR 1-3, PDGFR α and β and FGFR 1-3. Nintedanib has received regulatory approval in second line adenocarcinoma NSCLC in combination with docetaxel. In addition, nintedanib has been approved for the treatment of idiopathic lung fibrosis. Here we report the results from a broad kinase screen that identified additional kinases as targets for nintedanib in the low nanomolar range. Several of these kinases are known to be mutated or overexpressed and are involved in tumor development (DDR1 and 2, TRKA and C, Ret) as well as in fibrotic diseases (eg. DDRs). In tumor cell lines displaying molecular alterations in potential nintedanib targets, the inhibitor demonstrates direct anti-proliferative effects: in the NSCLC cell line NCI-H1703 carrying a PDGFRα amplification; the gastric cancer cell line KatoIII and the breast cancer cell line MFM223 both driven by a FGFR2 amplification; AN3CA (endometrial carcinoma) bearing a mutated FGFR2; the AML cell lines MOLM-13 and MV-4-11-B with FLT3 mutations; the NSCLC adenocarcinoma LC-2/ad harboring a CCDC6-RET fusion. However, potent kinase inhibition does not strictly translate into anti-proliferative activity as demonstrated in the TRKA dependent cell lines CUTO-3 and KM-12. Importantly, nintedanib treatment of NCI-H1703 tumor xenografts triggered effective tumor shrinkage, indicating the direct effect on the tumor cells on top of the antiangiogenic effect on the tumor stroma. These findings will be instructive to guide future genome-based clinical trials with nintedanib.