Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia

Abstract

Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified as a pan Bcr-Abl and Src kinase inhibitor. Further studies have indicated that it is a multitargeted inhibitor that is active on FGFRs, RET, AKT, ERK1/2, KIT, MEKK2 and other kinases. For this reason, the compound has been evaluated on several cancers in which these kinases play important roles, including thyroid, breast, ovary and lung cancer, neuroblastoma, rhabdoid tumours and in myeloproliferative disorders. Ponatinib is also being tested in clinical trials to evaluate its activity in FLT3-ITD acute myelogenous leukemia, head and neck cancers, certain type of lung cancer, gastrointestinal stromal tumours and other malignancies. In this review we report the most recent preclinical and clinical studies on ponatinib in cancers other than CML, with the aim of giving a complete overview of this interesting compound.

Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation

“…With the emergence of personalized medicine, the characterization of activators of SCLL, such as BCR-FGFR1, is critical in determining additional therapeutic targets. Although the use of TKIs to treat SCLL is becoming more commonplace, TKI treatment often results in drug resistance in patients, highlighting the need for additional therapies for SCLL (31).…”

Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia

“…A notable example is Thalidomide, a sedative initially used to treat leprosy, which was then repurposed for multiple myeloma, once it was identified to inhibit the angiogenesis induced by fibroblast and vascular endothelial growth factors (Richardson et al, 2002). Likewise, anti-cancer drugs such as Imatinib (Demetri et al, 2002), Sorafenib (Zhang et al, 2008), Crizotinib (Carpenter and Mosse, 2012), Gemcitabine (Zhang et al, 2017) and Ponatinib (Musumeci et al, 2018) are being successfully employed to treat various cancers apart from their original indication owing to their ability to target multiple pathways. Computational methods are also being used to identify new ways of tackling the BCR-ABL mutations by devising novel inhibitors that target the mutated clones (Banavath et al, 2014).…”

Critical role of the fibroblast growth factor signalling pathway in Ewing's sarcoma octamer‐binding transcription factor 4‐mediated cell proliferation and tumorigenesis

“…To confirm these results, we assessed the potential antiproliferative effects of other FGFR inhibitors: NVP-BGJ398 [63], ponatinib [64] and dovitinib [65]. GBS6 cells were incubated with increasing concentrations of NVP-BGJ398, ponatinib, or dovitinib.…”