Kazuhiro Katayama

Cyclin E1 (CCNE1) amplification is associated with poor prognosis of ovarian carcinomas across histological subtypes. Inhibitors targeting PLK1 or WEE1 are emerging as promising therapeutic agents for cancer treatment that disrupt the critical G2/M checkpoint, leading to cancer cell death. However, biomarkers that predict the response to these inhibitors are not well defined. Here, we evaluated the efficacy of the PLK1 inhibitor, volasertib, and the WEE1 inhibitor, adavosertib, along with the biomarker potential of cyclin E1 in ovarian cancer cells. Both inhibitors suppressed the proliferation of cyclin E1-overexpressing cells to a greater extent than that of cells exhibiting low cyclin E1 expression. TP53 silencing did not increase the sensitivity to these inhibitors. In cyclin E1-overexpressing cells, PLK1 inhibition reduced the proportion of cells in the G1 phase and increased those in the G2/M and sub-G1 phases. WEE1 inhibition reduced G1 phase cells without a clear peak in the S-G2/M phase and increased the sub-G1 phase cells. Both inhibitors suppressed the growth of cyclin E1-overexpressing tumors in vivo. Taken together, cyclin E1 overexpression, regardless of TP53 status, may serve as a predictive biomarker for the efficacy of these inhibitors, offering potential personalized treatment strategies for ovarian cancer.

ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

3′,4′,7‐Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP‐binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C‐5 and several kinds of capping moiety at the C‐7 hydroxy group, on the same 3′,4′‐dimethoxy‐substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP‐expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI₅₀). Of the synthesized compounds, the reversal effect of 5‐hydroxy‐3′,4′,7‐trimethoxyflavone (HTMF, RI₅₀ 7.2 nm) towards 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) was stronger than that of TMF (RI₅₀ 18 nm). Fluoro‐substituted 5‐fluoro‐3′,4′,7‐trimethoxyflavone (FTMF, RI₅₀ 25 nm) and monoglycosylated 7‐(β‐glucosyloxy)‐5‐hydroxy‐3′,4′‐dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di‐ and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP‐mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

Oncotarget | https://doi.org/10.18632/oncotarget.26045 Kazuhiro Katayama, Kohji Noguchi, Yoshikazu Sugimoto Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia