Abstract A153: Effect of the multikinase inhibitor TG02 in HER2-positive breast cancer.

Breast cancer represents a heterogeneous disease in which several distinct genetic and histopathological types have been defined. Depending on the latter, treatment is established based on the presence of estrogen or progesterone receptors, the transmembrane tyrosine kinase HER2, or the absence of these markers. One of the most aggressive subtypes of breast cancer is offered by the HER2 positive tumors. Treatment of these tumors is based on agents, such as the monoclonal antibody trastuzumab, or the small molecule tyrosine kinase inhibitor lapatinib, which target HER2. The incorporation of these therapies to HER2 positive tumors has improved patient outcome. However, in the metastatic setting HER2 positive tumors still represent an important oncological problem. Moreover, some patients are either primary resistant, or acquire resistance to anti-HER2 therapies along time. Therefore, novel therapies are required to fight the disease once disseminated and under instances of anti-HER2 resistance. In addition to HER2, several studies have involved other kinases in the pathophysiology of breast cancer. Because of these facts, we have investigated the antitumoral action of TG02 in HER2 positive breast cancers. TG02 represents a novel molecule with a unique kinase inhibitory sprectrum. TG02 targets several receptor tyrosine kinases, such as FLT3 and various cytosolic serine/threonine kinases, such as ERK5, p38, CDK1, CDK2, CDK5, CDK9. We used HER2 overexpressing cell lines SKBR3 and BT474 to explore the action of TG02 on these models of HER2 positive breast cancer. TG02 caused a dose-dependent decrease in MTT metabolization, an assay used to explore cellular proliferation and viability. IC50 values were in the low nanomolar range. The drug also potentiated the action of trastuzumab or lapatinib, with whom TG02 exerted a synergistic action, as indicated by the Chou and Talalay algorithm. In BT474 cells, which bear constitutively active ERK5, treatment with TG02 caused inhibition of ERK5 phosphorylation, at concentrations of 100 nM and above, without affecting HER2 tyrosine phosphorylation. Cell cycle analyzes indicated that TG02 caused a decrease in G0/G1, and an increase in the subG0 region of the histogram. This result suggested that TG02 could trigger apoptotic cell death in BT474 cells. In fact, treatment with TG02 caused a dose-dependent increase in the processing of PARP, which was accompanied by increased annexin V staining. Therefore TG02 may indice cell cycle effects together with an induction of apoptotic cell death. These data support further development of this compound for the treatment of HER2 positive tumors, especially in combination with other standard of care treatments used in these breast neoplasias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A153.