Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.

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Colorectal cancer (CRC) is one of the most prevalent malignant diseases and metastasis is the leading cause of poor prognosis in patients with CRC. Further knowledge of the molecular mechanism underlying metastasis in CRC and the identification of new therapeutic targets are needed. Yes-associated protein (YAP) is a transcriptional regulator that is important in tumorigenesis and tumor cell proliferation. The present study investigated whether YAP was crucial for CRC migration and invasion. The protein expression levels were detected via western blotting, and migration and invasion were analyzed by Transwell migration and invasion assays. Subsequently, YAP expression was silenced using small interfering RNA. The mRNA expression levels were detected via reverse transcription-quantitative PCR and cell viability was assessed via Trypan blue exclusion assay. The results revealed that YAP protein levels were associated with migration and invasion of CRC cells. Notably, YAP small interfering RNA inhibited the migration and invasion of DLD-1 cells. In addition, the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway inhibitor LY294002 suppressed the migration and invasion of DLD-1 cells by decreasing the expression of YAP. Notably, the present study demonstrated that verteporfin mediated the suppression of migration and invasion of DLD-1 cells due to the decreased expression of YAP. Therefore, targeting YAP may be valuable for developing therapeutic strategies against CRC, and verteporfin may be an effective therapy to suppress the migration and invasion of CRC.

Imatinib is the gold standard in the conventional treatment of chronic myeloid leukemia (CML). However, some patients become resistant to imatinib therapy. To overcome this resistance, second-generation (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) tyrosine kinase inhibitors (TKIs) have been developed and have been shown to be effective against refractory CML. Although these TKIs provide many benefits for patients with CML, advanced patients show resistance even to these TKIs. Therefore, novel therapeutic strategies are urgently needed for the treatment of TKI-resistant CML patients. AT9283 is a multi-targeted kinase inhibitor with potent activity against Janus kinase (JAK), Aurora kinases, and Abl. In the present study, we showed that AT9283 significantly decreased the cell viability of both TKI-sensitive and TKI-resistant CML cells as determined by trypan blue exclusion assay. In addition, cell cycle analysis, Annexin V assay, and caspase-3/7 activity assay revealed that AT9283 increased the cell population in the G2/M phase and induced apoptosis. We investigated the molecular mechanisms underlying the decrease in cell viability upon treatment with AT9283 by western blotting. Interestingly, our results showed that AT9283 inhibited the expression of Aurora A, Aurora B, and downstream Histone H3 phosphorylation. In contrast, we observed no changes in the levels of Bcr-Abl, signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), and Akt phosphorylation. In addition, we found that AMG900, a selective Aurora A and Aurora B inhibitor, increased the G2/M phase cell population and induced apoptosis via inhibition of Aurora A and Aurora B in both TKI-sensitive and TKI-resistant CML cells. Our studies show that Aurora A and Aurora B are promising therapeutic targets for TKI-sensitive and TKI-resistant CML, and AT9283 may have potential clinical applications for the treatment of TKI-resistant CML patients.