A new study supports the repurposing of the multitargeted kinase inhibitor nintedanib (Ofev®) for the treatment of gastrointestinal stromal tumors (GISTs) with de novo or acquired resistance to imatinib mesylate (Gleevec®).
“Nintedanib eliminated the adaptive response after KIT inhibition in imatinib-sensitive GISTs,” said the authors of the study published in Molecular Oncology.
They showed that nintedanib had potent activity against several primary gain-of-function mutations and secondary drug resistance mutations in KIT kinase. These included the primary mutations V559A/D/G and L576P, imatinib-resistant mutations in the ATP-binding pocket (V654A and T670I) and activation loops (D820E/G/Y, D816E/H/V, and A829P), and sunitinib-resistant mutations (D816H/V and A829P).
Most of the imatinib-resistant mutations localized in KIT’s activation loop and ATP-binding pocket, especially the gatekeeper mutation T670I, were more sensitive to nintedanib than to sunitinib (Sutent®), avapritinib (Ayvakit™), or ripretinib (Qinlock®).
The inhibitory effect of nintedanib on primary and secondary KIT kinase mutations suppressed KIT signaling pathway and cell proliferation in imatinib-resistant cells and preclinical models of GIST.
Additional studies in rodents confirmed the antitumor effect of nintedanib in KIT Δ560-578 and T670I mutation-dependent tumor models at well-tolerated doses. Moreover, it inhibited tumor growth on GIST882 tumor-bearing mice in a dose-dependent manner.
According to the authors, the antitumor effects of nintedanib are not only mediated by KIT kinase inhibition, but also by the potential inhibition of other kinases, such as the vascular endothelial growth factor and the platelet-derived growth factor receptor.
“However, nintedanib could not completely overcome the resistance mediated by MAP kinase activation via FGF signaling, which may be due to the low drug concentration in tumors or the weak inhibition of FGFR by nintedanib,” they said.
Liu J, Gao J, Wang A, et al. Nintedanib overcomes drug resistance from upregulation of FGFR signaling and imatinib‐induced KIT mutations in gastrointestinal stromal tumors. Mol Oncol. Published online February 23, 2022. doi:10.1002/1878-0261.13199