Table 1.
Targeted Mitotic Kinase |
Cmpd | Biological Effects in TNBC Models | Results from Clinical Studies on TNBC Patients or Other Tumors |
|
---|---|---|---|---|
In Vitro | In Vivo | |||
AURKB | Barasertib (AZD1152) | Reduction in mesenchymal traits [128]. | Inhibition of metastatic spreading of TNBC cells in immunodeficient murine models [128]. | Not available. Adequate levels of tolerance in patients with other advanced solid tumors, with observation of stable disease [144,145]. |
NEK2 | CMP3A | Induction of mitotic alterations in synergy with PTX [124]. Induction of sensitivity to PTX in resistant cell lines [124]. |
Enhancing antitumoral effects of PTX in TNBC cells xenografts and PDXs [124]. | Not available. |
JH295 | Inhibition of cells migratory and invasive properties [146]. | Not available. | Not available. | |
PLK1 | Rigosertib (ON-01910) |
Reactivation of Erα expression [147]. | Reduction in TNBC cell xenograft and PDX growth [147]. | Not available. Moderate toxicity in patients with other advanced solid tumors, with observation of stable disease [148,149]. |
Volasertib (BI-6727) |
Reactivation of Erα expression [147]. Increased DNA damage, mitotic arrest, and cell death [143,147]. |
Reduction in TNBC cell xenograft and PDX growth [147]. | Tolerable toxicity in patients with other advanced solid tumors, either alone or in combination with other chemotherapy, with partial antitumoral effects [150,151,152,153,154]. | |
BI-2536 | Induction of mitotic abnormalities and apoptosis [125,143,155]. Reactivation of Erα expression [147]. |
Reduced growth of TNBC PDXs and enhanced activity towards doxorubicin and cyclophosphamide antitumoral effects [125]. | Not available. Moderate toxicity and antitumoral effects in patients with other advanced solid tumors [156]. |
|
GSK461364 | Synergic antiproliferative and pro-apoptotic effects with docetaxel [157]. | Not available. | Not available. Mild toxicity and moderate antitumoral effects in patients with other solid tumors [158]. |
|
Onvasertib | Synergic antiproliferative and pro-apoptotic effects with docetaxel [157]. | Synergic antitumoral effects with PTX in TNBC cell xenografts [157]. | Not available. One ongoing trail testing the safety and effectiveness of its combination with PTX in locally advanced and metastatic TNBC (NCT05383196). |
|
MPS1/ TTK |
CFI-402257 | Inhibition of cell growth and induction of apoptosis and aneuploidy [159,160]. | Antitumoral effects against TNBC cell xenografts either as a single agent or in combination with carboplatin [160]. | Not available. Three ongoing trials testing the safety and antitumoral efficacy in different BC subtypes (NCT02792465, NCT03568422, NCT05251714). |
BOS172722 | Induction of cell death either as stand-alone treatment or in combination with PTX [161]. | Reduction in the growth of TNBC cell xenografts and PDXs and enhanced activity on the antitumoral effects of PTX [161]. | Not available. One ongoing trial testing its safety and tolerability, either alone or in combination with PTX, in advanced nonhematologic malignancies (NCT03328494). |
|
NTRC 0066-0 | Reduction in cell growth and induction of mitotic abnormalities [162]. | Reduction in TNBC cell xenograft growth as a single agent. Reduction in the growth of spontaneously developing murine tumors after combination with docetaxel [162]. | Not available. | |
BAY 1217389 | Inhibition of cell growth [163]. | Reduction in the growth of TNBC cell xenografts and PDXs and enhanced activity on the antitumoral effects of PTX [163]. | Considerable toxicity, without a therapeutic window, in association with PTX [164]. | |
WEE1 kinase |
Adavosertib (AZD1775) | Reduced cell growth both as a single agent and in association with capecitabine/5FU and/or ATR inhibitor [165,166,167]. | Reduced growth of TNBC xenografts and PDXs both as a single agent and in association with capecitabine/5FU and/or ATR inhibitor [165,166,167]. | Adequate levels of tolerance in TNB and other solid tumors, with stable disease in TNBC patients [168]. Not significant antitumoral effects in combination with cisplatin in metastatic TNBC [169]. |