TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors.
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ABSTRACT:
SUBMITTER: Oliveira EA
PROVIDER: S-EPMC8729257 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
| S-EPMC8616282 | biostudies-literature
Project description:Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
| S-EPMC3956616 | biostudies-literature
Project description:BackgroundMelanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance.MethodsIn this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested.ResultsIn general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA.Discussion and conclusionOur results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition.
| S-EPMC8163970 | biostudies-literature
Project description:The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in-depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance.
| S-EPMC6080616 | biostudies-literature
Project description:The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.
| S-EPMC3237573 | biostudies-literature
Project description:Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
| S-EPMC4765379 | biostudies-literature
Project description:Introduction:Breakthroughs in targeted therapy have significantly improved outcomes for many patients with advanced melanoma, including those with BRAFV600 mutant disease. Targeted therapy for BRAFV600-mutant metastatic melanoma includes combinations of BRAF inhibitors and MEK inhibitors, which improve response rates and prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, while durable responses have been observed, many patients develop acquired resistance to these drugs. Areas covered:Recent clinical trial updates and ongoing studies with targeted therapy for BRAF-V600 mutant melanoma are reviewed. Expert opinion:Although BRAF targeted therapy remains an effective treatment for BRAF-mutant for melanoma, ongoing trials are exploring combinations with other targeted therapeutics and immunotherapeutics to determine whether tumor responses can be prolonged, and these drugs are increasingly utilized in the neoadjuvant and adjuvant settings.
| S-EPMC6296476 | biostudies-literature
Project description:Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cells survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors. In addition, RIP1 kinase activity was not required for melanoma cells to survive BRAF/MEK inhibition as RIP1 mediated NF-κB activation through its intermediate domain. Collectively, our findings reveal that targeting RIP1 in combination with BRAF/MEK inhibitors is a potential approach in the treatment of the disease.
| S-EPMC5992182 | biostudies-literature
Project description:The treatment landscape in advanced melanoma is changing dramatically with the approval of new drugs. Vemurafenib was the first approved targeted agent for the treatment of BRAF-mutant advanced melanoma. However, treatment with a BRAF inhibitor is linked with acquired resistance occurring in half of the patients after approximately six months. Combination of MEK and BRAF inhibitor therapy results in extension of the time to resistance, translating into longer overall survival of treated patients. Similar clinical benefits are observed with therapy using antibodies against immune-checkpoint inhibitors in the same patient population. Due to the fact that results of randomised studies comparing these two treatment strategies back to back have not been presented yet, the best first and second line treatment option in patients with BRAF-mutant melanoma is unknown. Currently, phase 3 studies are also evaluating the efficacy of targeted therapy combined with immunotherapy in patients with BRAF-mutant and BRAF wild-type advanced melanoma. Identifying a biomarker for the selection of patients benefiting most from the treatment will be crucial for further survival improvement in patients with advanced melanoma.
| S-EPMC5885075 | biostudies-other
Project description:Drug resistance is a major obstacle in the targeted therapy of melanoma using BRAF/MEK inhibitors. This study was to identify BRAF V600E-associated oncogenic pathways that predict resistance of BRAF-mutated melanoma to BRAF/MEK inhibitors. We took in silico approaches to analyze the activities of 24 cancer-related pathways in melanoma cells and identify those whose activation was associated with BRAF V600E and used the support vector machine (SVM) algorithm to predict the resistance of BRAF-mutated melanoma cells to BRAF/MEK inhibitors. We then experimentally confirmed the in silico findings. In a microarray gene expression dataset of 63 melanoma cell lines, we found that activation of multiple oncogenic pathways preferentially occurred in BRAF-mutated melanoma cells. This finding was reproduced in 5 additional independent melanoma datasets. Further analysis of 46 melanoma cell lines that harbored BRAF mutation showed that 7 pathways, including TNF?, EGFR, IFN?, hypoxia, IFN?, STAT3, and MYC, were significantly differently expressed in AZD6244-resistant compared with responsive melanoma cells. A SVM classifier built on this 7-pathway activation pattern correctly predicted the response of 10 BRAF-mutated melanoma cell lines to the MEK inhibitor AZD6244 in our experiments. We experimentally showed that TNF?, EGFR, IFN?, and IFN? pathway activities were also upregulated in melanoma cell A375 compared with its sub-line DRO, while DRO was much more sensitive to AZD6244 than A375. In conclusion, we have identified specific oncogenic pathways preferentially activated in BRAF-mutated melanoma cells and a pathway pattern that predicts resistance of BRAF-mutated melanoma to BRAF/MEK inhibitors, providing novel clinical implications for melanoma therapy.
| S-EPMC3906238 | biostudies-literature