Knockdown of P53 lead to increased cellular sensitivity to TAI 1 in the cells carrying wild type P53. These results indicate that the status of RB and P53 may affect the activity of Hec1 targeted inhibitor TAI 1 on can cer cells, and cells with a loss of functional RB or P53 may have an increased sensitivity to Hec1 targeted inhibitors. Differential Hec1 expression in clinical cancer subtypes Genome wide expression profile analysis has shown that Hec1 is upregulated in lung, colorectal, liver, breast, and brain tumors and that Hec1 expression correlates with tumor grade and prognosis. To determine whether HEC1 expression varies between cancer subtypes from the same tissue or organ, the gene expression data of NDC80 between adenocarcinoma and squamous carcinoma was studied for lung cancer.
As shown in Figure 9A, NDC80 expression is significantly higher in squamous cell carcinoma of lung than adenocarcinoma in all three independent datasets. One way hierarchical cluster analysis consistently showed that NDC80, NEK2, NUF2 and SPC25 were reproducibly clustered together in three different gene expression datasets. All these four genes showed higher expression in squa mous cell supplier Mupirocin carcinoma of lung. The results indicate that different subtypes of lung cancer could respond differ ently to the treatment of Hec1 inhibitor. The predictabil ity of response to Hec1 targeted treatment according to Hec1 associated gene expression remains to be further studied, however, our results suggest such consideration for HEC1 or related gene expression may be an import ant factor in the design of personalized Hec1 targets treatment of cancers.
Discussion selleckchem This study explored the potential of the improved anti cancer agent targeting Hec1 for clinical development and utility. The potency, safety, synergistic effect, markers for response and clinical relevance was evaluated using in vitro, in vivo, and database analysis methods. Ever since Hec1 was discovered and characterized, the possibility that this may be a good molecular target was discussed. Hec1 is an oncogene that when overexpressed in transgenic mice leads to tumor formation. The differential expression profile of Hec1 in cancer cells in comparison to normal non actively dividing cells further supports the suitability of this target for anticancer treatment.
The current study shows a small molecule with largely improved potency range enabling the pre clinical development of a Hec1 targeted small molecule. The structure activity relationship is demonstrated for over 200 analogues of the Hec1 targeted small molecule. The improved Hec1 targetd small molecule TAI 1 in hibits the growth of a wide spectrum of cancer cell lines in vitro. Interestingly, a small number of cell lines were resistant to TAI 1, suggesting that there may be changes in signaling pathways that allow cells to bypass Hec1 in hibitor induced cell death.