Dovitinib (TKI-258, CHIR-258)

Dovitinib (TKI258, CHIR-258) is a multitargeted receptor tyrosine kinase inhibitor against FLT3, KIT, FGFR, VEGFR, PDGFRα and PDGFRβ with IC50 of 1 nM, 2 nM, 8-9 nM, 8-13 nM , 210 nM and 27nM, respectively [1].

The viability of ZNF198-FGFR1 or BCR-FGFR1 cells was specifically inhibited by TKI258 with IC50 values of 150 nM or 90 nM. The phosphorylation of ERK and STAT5 genes was inhibited by TKI258 in dose dependent manner. TKI258 also specifically inhibited proliferation and survival of the FGFR1OP2-FGFR1-positive KG1 and KG1A cell lines, increasing levels of apoptosis [2]. In hepatocellular carcinoma (HCC) cells, the combination of TKI258 and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. TKI258 inhibited phosphorylation of STAT3 and subsequently reduced the protein levels of Mcl-1, Survivin and Cylcin D1. Co-treatment of TRAIL and TKI258 increased the activity of SHP-1 [3]. Inhibition of FGFR3 with TKI258 decreased waldenstr?m macroglobulinemia (WM) cell survival, increased apoptosis, and induced cell cycle arrest. TKI258 reduced the interaction of WM to bone marrow element, and reversed its proliferation. TKI258 had an additive effect with other drugs [4].

In vivo, the combination of tigatuzumab and TKI258 inhibited Huh-7 xenograft tumor growth [3]. TKI258 reduced WM tumor progression [4].

References:
[1]. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8.
[2]. Chase A, Grand FH, Cross NC. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007 Nov 15;110(10):3729-34.
[3]. Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol. 2012 Mar 15;83(6):769-77.
[4]. Azab AK, Azab F, Quang P, Maiso P, Sacco A, Ngo HT, Liu Y, Zhang Y, Morgan BL, Roccaro AM, Ghobrial IM. FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. Clin Cancer Res. 2011 Jul 1;17(13):4389-99.

Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR(+), HER2(-) breast cancer that had progressed during or after prior endocrine therapy.[Pubmed:28183331]

Breast Cancer Res. 2017 Feb 10;19(1):18.

BACKGROUND: Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in

Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications.[Pubmed:28342996]

Transl Oncol. 2017 Jun;10(3):357-366.

Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors.[Pubmed:27681579]

Cancer Chemother Pharmacol. 2016 Nov;78(5):921-927.

PURPOSE: A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer. METHODS: In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase. RESULTS: A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule --> tablet, n = 88; tablet --> capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUClast, 0.95 (90 % CI 0.88-1.01); C max, 0.98 (90 % CI 0.91-1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients. CONCLUSIONS: Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.[Pubmed:28714373]

Tumour Biol. 2017 Jul;39(7):1010428317707372.

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.

Activity of fibroblast growth factor receptor inhibitors TKI258, ponatinib and AZD4547 against TPRFGFR1 fusion.[Pubmed:28138694]

Mol Med Rep. 2017 Mar;15(3):1024-1030.

8p11 myeloproliferative syndrome (EMS) is a rare disease characterized by the constitutive activation of fibroblast growth factor receptor 1 (FGFR1). To date, four cases of EMS with the chromosomal translocation, t(1;8)(q25;p11.2), have been reported. In the present study, TPRFGFR1expressing Baf3 cells were established and confirmed by polymerase chain reaction. To identify the most promising drug for EMS, the activities and associated mechanism of three tyrosine kinase inhibitors (TKIs), TKI258, ponatinib and AZD4547, against TPRFGFR1 were tested by MTT assay, flow cytometry and western blot. The data demonstrated that TPRFGFR1 was localized in the cytoplasm, and was able to transform interleukin-3-dependent hematopoietic Baf3 cells into growth factorindependent cells. All of the three TKIs markedly inhibited the proliferation of TPRFGFR1expressing Baf3 cells, and the activation of FGFR1 and the downstream signaling molecules, extracellular signalregulated kinase 1/2, phospholipiase Cgamma and signal transducer and activator of transcription 5. AZD4547 was the most efficient drug, and TKI258 was the least. By contrast, no significant difference was found among the three drugs on their effect on cell apoptosis. Taken together, the data obtained in the present study suggested that AZD4547 had increased potency, compared with TKI258 and ponatinib, for the treatment of EMS.

Dovitinib (TKI258; CHIR-258) is a multi-targeted tyrosine kinase inhibitor with IC50s of 1, 2, 8/9, 10/13/8, 27/210 nM for FLT3, c-Kit, FGFR1/3, VEGFR1/2/3 and PDGFRα/β, respectively.

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