Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We use this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 prosurvival proteins, defeat resistance and avoid relapse to therapy. Indeed, we found that BH3 mimetics that selectively target BCL-xL and MCL-1 synergistically enhance the effect of the clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft (PDX) model and observed a reduction on tumor growth with a tendency to its stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. Finally, we identified the molecular mechanism by which RMS cells acquire resistance to vincristine: through the antiapoptotic protein MCL-1 for which we observed an enhanced binding between MCL-1 and BID after drug exposure, which is suppressed by the sequential addition of S63845. In conclusion, our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for BH3 mimetic combination with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency and decrease undesired secondary effects. Alcon et al.

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

“…S1i). In SKBR-3 cells, which express the highest cellular levels of FASN (up to 28% by weight of the cytosolic proteins) yet described in human established cell lines [26,27,51,52], a clear apoptotic synergism was observed when C75 was added to navitoclax/ABT-263, which had no impact against SKBR-3 cells as single agent (Fig. 4b).…”

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

“…Interestingly, this study showed that the observed acquired antiapoptotic dependence to the BRAF inhibitor dabrafenib was not mediated by an increase in MCL1 expression, but through a NOXA mRNA destabilization leading to protein decrease (151). Other novel therapeutic combinations with BH3 mimetics were recently identified using this approach in NSCLC (200), breast cancer (123,158,201,202), esophageal cancer/ mesothelioma (203), and pediatric cancers (146,204), among others. Depicting the complexity of these prosurvival adaptations and antiapoptotic cross-talk is key to accurately identifying the right drug combination and the optimal sequential administration to maximize the cytotoxic effect in tumors.…”

“…Apart from the previously cited examples of BH3 mimetic combinations in hematologic malignancies, multiple reports demonstrated that BCL2/BCLXL inhibition combined with conventional chemotherapy was effective against many solid tumors, including breast cancer, ovarian cancer, neuroblastoma, NSCLC, and many others (32,44,130,(139)(140)(141)(142)(143)(144). Also, as new compounds emerge, MCL1 inhibition has been successfully used in preclinical studies to boost standard-of-care treatments in hepatocellular carcinoma (68), breast cancer (145), ovarian cancer (130), and rhabdomyosarcoma (146), among others.…”

BBB-on-a-chip with Integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease

“…To evaluate the ability of GNR-PEG-Ang2/D1 to cross the BBB, it was functionalized with the fluorophore Alexa647 and injected into the endothelial channel of the BBB-oC and fluorescent images were taken. Since Ang2 can penetrate the BBB by receptor-mediated endocytosis due to high LRP1 binding affinity, the expression of LRP1 in EC was confirmed by western blot [63] (Supplementary Figure S4) [65]. To evaluate the role of Ang2 in the entrance, nanoparticles without the shuttling peptide (GNR-PEG-D1) were used as control.…”

“…Since Ang2 can penetrate the BBB by receptor-mediated endocytosis due to high LRP1 binding affinity, the expression of LRP1 in EC was confirmed by western blot [63] (Supplementary Figure S4) [65]. To evaluate the role of Ang2 in the entrance, nanoparticles without the shuttling peptide (GNR-PEG-D1)…”