Oncotarget
-
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. ⋯ Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.
-
We did a meta-analysis to compare the efficacy and safety of neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiotherapy (CCRT) versus CCRT with or without adjuvant chemotherapy (AC) for patients with locoregionally advanced nasopharyngeal carcinoma based on randomized controlled trials. ⋯ Our meta-analysis confirmed that the addition of NACT to CCRT significantly improved PFS and OS versus CCRT with or without AC for locoregionally advanced nasopharyngeal carcinoma. These results may alter the standard of care - CCRT with or without AC, for locoregionally advanced nasopharyngeal carcinoma.
-
Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. ⋯ In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.
-
FLT3 mutation is found in about 30% of acute myeloid leukemia (AML) patients and is associated with a poor prognosis. Several FLT3 inhibitors are undergoing investigation, while their clinical efficacies were lower than expected and several resistant mechanisms to FLT3 inhibitors have been demonstrated. Although most AML cells harboring FLT3 mutation co-express wild-type (Wt)-FLT3, it is not fully understood how Wt-FLT3 expression is associated with the resistance to FLT3 inhibitors. ⋯ Furthermore, FL-induced activation of Wt-FLT3-MAPK axis was the dominant pathway for the resistance, and the glycosylation of Wt-FLT3 was also vital for FL-dependent kinase activation and following resistance to FLT3 inhibitors. Thus, we clarified the importance of co-expressing Wt-FLT3 in resistance to FLT3 inhibitors. These findings provide us with important implications for clinical application and new strategies to improve clinical outcomes of FLT3 inhibitors.
-
Aiming for an adoptive natural killer (NK) cell therapy, we have developed a novel protocol to expand NK cells from peripheral blood. With this protocol using anti-human CD16 antibody and interleukin (IL)-2, NK (CD3-CD56+) cells could be expanded about 4000-fold with over 70% purity during a 21-day culture. The expanded NK (exNK) cells were shown to be highly cytotoxic to multiple myeloma (MM) cells (RPMI8226) at low NK-target cell ratios. ⋯ In a murine model of MM, transfusion of exNK cells, exNK+PD1-blockage, and exNK plus intratumor injection of anti-PD-L2 antibody (exNK+PD-L2 blockage) all significantly suppressed tumor growth and prolonged survival of the myeloma mice. Importantly, exNK+PD1-blockage presented more efficient therapeutic effects. Our results suggest that the NK cell expansion protocol with PD1 blockade presented in this study has considerable potential for the clinical application of allo- and auto-NK cell-based therapies against malignancies.