Molecular‐targeting therapies against quantitative abnormalities in gene expression with malignant tumors

Abstract

Genetic mutations in exons of oncogenes and tumor‐suppressor genes causing qualitative abnormalities result in activation of the oncogenes and inactivation of the tumor‐suppressor genes, thereby causing cancer. In contrast, we have previously demonstrated that decreases in the RB promoter activity by genetic or epigenetic abnormalities can also cause carcinogenesis. In addition, activation and inactivation of a variety of oncogenes and tumor‐suppressor genes finally cause quantitative abnormalities in gene expression. Interestingly, we discovered effective molecular‐targeting agents, such as a novel MEK inhibitor, trametinib, by screening for agents upregulating the expression of cyclin‐dependent kinase inhibitors. In the present review, we focused on the quantitative abnormalities in gene expression with carcinogenesis, and discuss the importance of normalizing the quantitative abnormalities in gene expression with several molecular‐targeting agents.

Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells

“…We discovered two potent MEK inhibitors, trametinib and CH5126766, by the cell-based screening in collaboration with pharmaceutical companies [ 33 ]. Fortunately, it has been commonly recognized that trametinib is indispensable for treatment for BRAF mutated melanoma.…”

“…However, the apoptotic resistance to MEK inhibitors is one of the most difficult problems in the expansion of the indication for MEK inhibitors. Considering that we originally discovered these MEK inhibitors by screening for RB-reactivating compounds [ 33 ], it is no wonder that they cannot induce apoptosis well because RB activation restrains the pro-apoptotic activity of E2F1 [ 34 ]. We here demonstrated that the blockade of the mevalonate pathway using statins overcomes the apoptotic resistance to MEK inhibitors with suppression of Akt activation (Figure 7 ).…”

Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

“…That is, PHB2 is also located in membrane lipid rafts, and forms a complex with RAS and CRaf, leading to the activation of the MAPK cascade [ 33 , 34 ]. Considering that the inhibition of the MAPK cascade results in the activation of RB protein and the suppression of the transcriptional activity of E2F1 [ 35 , 36 ], rabdosianone I-bound PHB2 in the plasma membrane may suppress TS expression by blocking the MAPK cascade. Thus, the subcellular localization of PHB2-bound rabdosianone I should be further examined to clarify the complete mechanism(s) of PHB2-mediated regulation of TS mRNA.…”

Novel RAF/MEK inhibitor CH5126766/VS‐6766 has efficacy in combination with eribulin for the treatment of triple‐negative breast cancer

“…To develop a new strategy for the treatment of TNBC, we investigated whether the RAF/MEK inhibitor CH5126766, which was derived from our established cell‐based assay 9 and now also known as VS‐6766, enhanced the antiproliferative effects of eribulin in TNBC cells. The efficacy of CH5126766 against solid tumors with activated MAPK pathways has already been assessed in a phase I study (ClinicalTrials.gov NCT02407509) 10 .…”