PLX4720

We demonstrated that TERT is exported from the nucleus in response to OS induced either from H2O2 or the BRAF inhibitor PLX4720...In conclusion, our data indicate that extra-nuclear TERT is involved in reducing the effect of excessive OS, thus promoting cancer cell survival. Extra-nuclear TERT may thus represent a marker of cancer progression and a possible therapeutic target in PTC.

By means of oncoPredict, MG-132, BMS-536924, PLX-4720, and AZD6482 were identified as potential sensitive drugs for high-risk patients, of which MG-132 was particularly recommended for high-risk patients. We performed in vitro experiments to explore the anti-glioma effect of MG-132, and the results demonstrated MG-132 could inhibit the proliferation and migration of glioma cells. Our findings show that CCC genes are associated with the prognosis and immune infiltration of LGG and provide possible immunotherapeutic and novel chemotherapeutic strategies for patients with LGG based on the risk signature.

We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-β, and was enhanced in TRAF2-/- cells...We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2-/- in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-β-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation.

The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.

BVE‐Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β‐catenin/KDM4A inhibitor PKF118‐310. In summary, we have identified several targetable genes/pathways in thyroid cancer metastasis. Given the complexity of metastatic cells in evasion of host immune response, simultaneously targeting more than one of these pathways (PDL1, Mertk, IL6, COX‐1/Tbxas1‐TXA2) may be warranted to achieve better therapeutic effect.

It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.

This study demonstrates that targeting SPI1 to block transcription of the MIR222HG cluster helps to reduce radioresistance and combat the immunosuppressive microenvironment in GBM. PLX-4720 is a potential GBM drug and radiosensitizer.

Importantly, through a "drug repurposing" strategy, we uncovered that PLX4720, a small molecular selective inhibitor of B-RafV, is a novel SRMS inhibitor that can potently boost platinum efficacy in ovarian cancer in vitro and in vivo. Therefore, targeting SRMS with PLX4720 holds the promise to improve the efficacy of platinum-based chemotherapy and overcome chemoresistance in ovarian cancer.

We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients.

Our study elucidated the possible role of TRP family genes in cancer progression and provided insights for further studies on TRP family genes as potential pan-cancer targets to develop diagnostic and therapeutic strategies.

Soranjidiol, Thiamine, Lucidin, 2-Methyl-1,3,5-Trihydroxyanthraquinone and Rubiadin were the five top-scoring compounds ranging from -8.39 to -8.22 kcal/mol, however, the standard ligand, PLX4720, scored -11.26 kcal/mol...These five compounds, unlike the standard compound, demonstrated adequate druglike properties and good safety profiles. Therefore, further studies should be undertaken so as to develop them into drugs against HCC.Communicated by Ramaswamy H. Sarma.

Tumor-bearing mice were treated with (1) doxorubicin (intratumoral) chemotherapy for MCA-205, (2) BRAF-inhibitor PLX4720 (oral gavage) targeted therapy for 5555 Braf, and (3) X-ray radiotherapy for B16 LA-OVA-mCherry. Our results point to cDC1 and DNGR-1 as decoders of ICD and to sGSN as a negative regulator of such decoding, highlighting sGSN as a possible target in cancer treatment. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function.

Mice received doxorubicin (intratumoural), BRAF-inhibitor PLX4720 (oral gavage), or X-ray irradiation. Tumours enriched in DNGR-1 may be potential avenues where targeting sGSN could be impactful. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function to unleash DNGR-1-dependent cross-presentation as a component of more effective combinatorial treatment regimens.

Besides, high-risk KIRC patients might benefit from ABT888, AZD6244, AZD7762, Bosutinib, Camptothecin, CI1040, JNK inhibitor VIII, KU55933, Lenalidomide, Nilotinib, PLX4720, RO3306, Vinblastine, and ZM.447439; however, low-risk populations might benefit from Bicalutamide, FH535, and OSI906. Finally, calibration curves were used to validate the nomogram with a satisfactory predictive survival probability. In conclusion, this research provides useful insight that can aid and guide clinical practice and scientific research.

The treatment of BRAF and MEK inhibitor, PLX4720 and PD0325901, decreased the expression of miR-222-3p in B-CPAP but not in TPC-1. Besides, in situ hybridization (ISH) and IHC analysis of PTC clinical samples confirmed the correlation between the expression of miR-222-3p and Snail. These results showed miR-222-3p conduced more aggressive clinical manifestation of PTC by promoting Snail-induced EMT.

Treatment with Sorafenib and UO126 inhibited proliferation of Ba/F3-SOX5-RAF1 cells in the absence of IL3 but not the PLX 4720, a specific inhibitor of BRAF. These results indicate that SOX5-RAF1, a driver event for CMN development, has oncogenic capacity. Thus, sequencing of CMN transcriptomes may lead to identification of this druggable fusion and to interfere with the progression towards melanoma.

Taken together, these results suggest that autophagy may be an important mechanism of acquired resistance to BRAF inhibitors. Thus, targeting autophagy may be suitable for the treatment of tumors resistant to BRAF inhibitor.

The BRAF signature may better help guide targeted therapy for melanoma, and such a framework can be applied to other cancers and mutations to provide more information than mutation status alone.

We reveal that the inhibition of BRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells...Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by BRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting BRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of BRAF-positive thyroid tumours.

Treatment with dual β-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1wt tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo. These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAFV600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup can benefit from BRAF-mediated therapeutic interventions.

Using an animal model of BRAF inhibitor-resistant melanoma, we show that co-treatment with the BRAF inhibitor, PLX4720, and...APis unique because it targets the polyamine transport system in BRAF inhibitor-resistant CSCs and also blocks CXCR4 signaling in invasive melanoma cells and pro-tumorigenic macrophages.

Collectively, our research provides a compelling rationale for resistance to BRAF inhibitor in melanoma, and the patient might benefit from the combinatorial therapy of BRAF inhibitors and lncRNA TSLNC8.

Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. Combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than mono-treatments. Additional pathways could be further exploited in novel efficient combinatorial treatment protocols with BRAFi.

We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.

Drug sensitivity analysis revealed BRAF inhibitor PLX-4720 was sensitive in both MM cells...ACSM3 was potentially associated with immune exclusion in MM. Further validation was warranted in future studies.

Here, we show that the combination of PLX4720 (BRAFV600E inhibitor) and intratumoral oncolytic herpes virus HSV1716 led to a significant tumor reduction and improved survival over single-agent treatment in a murine BRAFV600E melanoma model. Using Tocky, we are identifying specific immune subsets that are stimulated following therapy and the real-time dynamics of antigen recognition and subsequent cell activation. These findings form the basis of future testing of drug-virus combinations in an effort to identify potent cytotoxic, as well as immuno-modulatory, strategies and their detailed mechanism of action.

Cell lines carrying V600E mutation at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.

The small molecule inhibitor vemurafenib, also known as PLX4032, and its tool analog PLX4720 were designed to inhibit constitutively active BRAF V600E, yet they also have potent effects against PTK6. Using saturation transfer difference NMR and molecular docking, we demonstrate that vemurafenib binds in the active site of PTK6 inhibiting its activation. These structural studies provide insight into the PTK6-vemurafenib complex which can be utilized for further refinement chemistry while functional studies demonstrate that active PTK6 is a viable drug target in prostate cancer.

Taken together, our results indicate that S100A9 might be functionally involved in development of resistance to BRAF inhibitors and might be a target for melanoma therapy in the future.

Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.