In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2830-2830
Kurzfassung:
Breast cancer (BC) is a heterogeneous disease in which several distinct genetic and histopathological types have been defined. Triple-negative breast cancer (TNBC) lacking ER/PR and HER-2 is the most aggressive and untreatable form. In the case of HER2+ tumors, and despite the emergence of trastuzumab and lapatinib, in the metastatic setting these tumors remain incurable due to the innate or acquired drug resistance. A number of kinases are implicated in the proliferation and survival of breast cancer cells. Here, we characterize the antitumor activity of the multikinase inhibitor TG02 in TNBC and HER2+ BC. TG02 is a novel drug with a unique kinase inhibitory spectrum, targeting both the cell cycle regulatory CDKs 1/2 and the transcriptional regulators CDKs 7/9, along with the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5, all within a narrow low nanomolar potency range. In panels of breast cancer cell lines, TG02 was potently and consistently antiproliferative at low (100nM) and proapoptotic at moderate (250-1000nM), clinically-achievable concentrations. In TNBC cells, the drug usually induced a G2/M arrest, whereas blockade of cell cycle progression at the G1/S boundary was more common in HER2+ lines. Simultaneous multikinase inhibition was demonstrated in several cellular models, showing that cell cycle arrest induced by inhibition of CDK1 and CDK2 progresses to apoptosis associated with profound depletion of the short-lived survival proteins of the Bcl-2 and IAP families downstream of CDK9-dependent loss of RNA polymerase II-driven transcription. TG02 was synergistic in combination with chemotherapy in TNBC models in vitro and in vivo and with trastuzumab and lapatinib in HER2-overexpressing cell lines. A majority of TNBC and HER2+ lines expressed constitutively active ERK5, which was efficiently inhibited by TG02 and may contribute to the antitumor activity of the drug. A robust DNA damage response including CHK1/2 activation and formation of H2AX foci was induced in TNBC cells, presumably due to inhibition of CDK5 by TG02, so we will also report on the mechanism-based combination of TG02 with PARP inhibitors in this setting. These data support clinical development of this compound for the treatment of TNBC and HER2+ BC, especially in combination with standard of care treatments used in these breast neoplasias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2830. doi:1538-7445.AM2012-2830
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-2830
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2012
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
Permalink