scholarly journals PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Antoni Ribas ◽  
Alain Algazi ◽  
Paolo A. Ascierto ◽  
Marcus O. Butler ◽  
Sunandana Chandra ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Advanced Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Oncogenic Signaling ◽  
Open Label ◽  
Mitogen Activated Protein

AbstractCombining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.

scholarly journals Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

2020 ◽  
Vol 21 (6) ◽  
pp. 2167
Author(s):  
Jingxuan Zhu ◽  
Congcong Li ◽  
Hengzheng Yang ◽  
Xiaoqing Guo ◽  
Tianci Huang ◽  
...  
Keyword(s):  
Molecular Dynamic ◽  
Conformational Changes ◽  
Computational Study ◽  
Md Simulations ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Lung Cancers ◽  
Mitogen Activated Protein ◽  
Alk Positive

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

scholarly journals Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

2014 ◽  
Vol 32 (21) ◽  
pp. 2248-2254 ◽  
Author(s):  
Siwen Hu-Lieskovan ◽  
Lidia Robert ◽  
Blanca Homet Moreno ◽  
Antoni Ribas
Keyword(s):  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf Inhibitors ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
Prolonged Duration ◽  
Trial Testing ◽  
Mitogen Activated Protein ◽  
Braf Mutant

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by pretreatment with the MEK inhibitor selumetinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5509-5509 ◽  
Author(s):  
Alan Loh Ho ◽  
Rebecca Leboeuf ◽  
Ravinder K. Grewal ◽  
Eric Jeffrey Sherman ◽  
Desiree Deandreis ◽  
...  
Keyword(s):  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Pet Scan ◽  
Mitogen Activated Protein Kinase ◽  
Iodine Uptake ◽  
Sodium Iodide Symporter ◽  
Serum Thyroglobulin ◽  
Thyroid Cancers ◽  
Positron Emission ◽  
Mitogen Activated Protein

5509^ Background: Therapies for radioactive iodine (RAI)-refractory thyroid cancers of follicular origin (TC-FCO) are desperately needed. TC-FCO mouse models show that blocking mitogen-activated protein kinase (MAPK) signaling with a MAP kinase kinase 1/2 (MEK1/2) inhibitor increases sodium iodide symporter expression and iodine incorporation. This 20 patient (pt) pilot study aimed to evaluate if the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142866) can reverse RAI-refractoriness in TC-FCO pts (NCT00970359). Methods: RAI-refractory TC-FCO disease was defined as: 1) non-RAI-avid lesion/s on a diagnostic or post-therapy RAI scan, 2) RAI-avid lesion/s that was stable or increased in size after RAI therapy, or 3) fluorodeoxyglucose (FDG)-avid lesion/s by positron emission tomography (PET) scan. rhTSH-stimulated lesional dosimetry with 124I PET was performed prior to and after 4 weeks of treatment with selumetinib (75 mg orally bid). If the second 124I PET scan predicted a lesional RAI dose of > 2000 cGy, therapeutic RAI was administered while on the drug. Primary endpoints were to evaluate changes in tumor iodine uptake and RECIST response after RAI therapy; changes in serum thyroglobulin (TG) after RAI was a secondary endpoint. Results: 24 pts were enrolled, 22 eligible, and 20 evaluable. For the 20 evaluable pts, median age was 61 (range 44-77 yrs), 11 were men. 19 pts had tumors analyzed for BRAF and N-,K- RAS mutations. 8 pts had BRAF mutant (MUT), 11 BRAF wild-type (WT) tumors; 1 pt to be analyzed. Selumetinib increased 124I uptake in 12 of the 20 pts (4 of 8 BRAF MUT; 8 of the 12 other pts). The 8 of those 12 pts achieving sufficient iodine avidity to warrant RAI therapy included all 5 pts known to be NRAS MUT to date and 1 BRAF MUT pt. Of the 7 pts who have received RAI, 5 had partial responses (PRs); 2 stable disease (SD). Mean percent reduction in TG in this group (pre- vs 2 months post- RAI) was 91%. No > grade 2 CTCAE toxicities attributable to selumetinib were observed. 1 pt was diagnosed with myelodysplastic syndrome > 51 weeks after RAI (unrelated to selumetinib). Conclusions: Selumetinib can enhance iodine uptake in a subset of RAI-refractory TC-FCO and may be particularly effective for RAS MUT tumors.

Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6023-6023 ◽  
Author(s):  
Vivek Subbiah ◽  
Robert J. Kreitman ◽  
Zev A. Wainberg ◽  
Jae Yong Cho ◽  
Jan H.M. Schellens ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Credible Interval ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Open Label ◽  
Dismal Prognosis

6023 Background: ATC is a rare, aggressive malignancy with a dismal prognosis. Median overall survival (OS) is < 6 mo. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma and lung cancer. One-fourth of ATCs harbor activating BRAF V600E mutations; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated ATC. Methods: In this phase 2, open-label trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), OS, and safety. We report data from the ATC cohort. Results: 16 pts with BRAF V600E–mutated ATC had evaluable data with a median follow-up time of 47 wk (range 4-120 wk). BRAF V600E mutations were centrally confirmed in 15/16 pts. Median age was 72 y; all 16 pts had undergone prior tumor radiation and/or surgery and 6/16 pts (38%) had received ≥1 prior line of systemic therapy. Investigator-assessed confirmed ORR was 69% (11/16; 95% CI, 41%-89%), with 7/11 responses ongoing at the time of data cut. The Bayesian estimate of ORR was 69% (95% credible interval, 47%-87%) with a 100% probability that this ORR exceeded the 15% historical RR. Median DOR, PFS, and OS were not estimable due to insufficient progression and death events. Kaplan-Meier estimates of DOR, PFS, and OS at 12 mo were 90%, 79%, and 80%, respectively. The safety population comprised 100 pts enrolled in 7/9 histologies. Among all pts, 92% had an AE. Common AEs of any grade for all histologies were fatigue (38%), pyrexia (37%), and nausea (35%). In the ATC cohort, the most common grade 3/4 events were hyponatremia (19%), pneumonia (13%), and anemia (13%). Conclusions: D+T combination therapy significantly improved outcomes in ATC with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC. Clinical trial information: NCT02034110.

scholarly journals The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells

2006 ◽  
Vol 203 (7) ◽  
pp. 1651-1656 ◽  
Author(s):  
Hidetoshi Sumimoto ◽  
Fumie Imabayashi ◽  
Tomoko Iwata ◽  
Yutaka Kawakami
Keyword(s):  
Immune Evasion ◽  
Cellular Proliferation ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Mek Inhibitor ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Factor Α

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAFV600E). MEK inhibitor U0126 or RNA interference (RNAi) for BRAFV600E decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor α by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAFV600E RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAFV600E and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.

scholarly journals P.022 Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma

2019 ◽  
Vol 46 (s1) ◽  
pp. S19 ◽  
Author(s):  
A Zaloum ◽  
JR Falet ◽  
A Elkrief ◽  
C Chalk
Keyword(s):  
Protein Kinase ◽  
Myasthenia Gravis ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Mitogen Activated Protein

Background: Inhibitors of BRAF and MEK, enzymes in the mitogen-activated protein kinase (MAPK) pathway, are now widely used in the treatment of metastatic melanoma. We report a case of acetylcholine receptor (AChR) antibody-positive myasthenia gravis developing after exposure to dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Methods: A 68-year-old man presented with dysarthria, dysphagia, cough, dyspnea, and fever. Examination revealed fatigable ptosis and proximal muscle weakness. He had started dabrafenib and trametinib for metastatic melanoma two weeks prior. He was diagnosed with myasthenia gravis and superimposed aspiration pneumonia. AChR antibodies were positive. Dabrafenib and trametinib were stopped. He improved rapidly with pyridostigmine alone, and remained free of myasthenic symptoms for the next two months. Another course of dabrafenib and trametinib was given, and seven weeks later, his myasthenic symptoms recurred. Pyridostigmine produced only partial improvement, and treatment with intravenous immunoglobulin and prednisone was initiated. Results: We are unaware of prior reports of an association between BRAF/MEK inhibitors and seropositive myasthenia gravis. The development of myasthenic symptoms twice after BRAF/MEK inhibitor exposure suggests that the association is more than coincidental. Conclusions: Myasthenia gravis may be a complication of treatment of melanoma with dabrafenib and trametinib. The mechanism by which this occurs is unknown.

scholarly journals Ocular changes in metastatic melanoma patients treated with MEK inhibitor cobimetinib and BRAF inhibitor vemurafenib

2018 ◽  
Vol 52 (2) ◽  
pp. 213-219 ◽  
Author(s):  
Ana Ursula Gavric ◽  
Janja Ocvirk ◽  
Polona Jaki Mekjavic
Keyword(s):  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Retinal Layers ◽  
Ocular Symptoms ◽  
Ocular Side ◽  
Mitogen Activated Protein ◽  
Melanoma Patients ◽  
Murine Sarcoma

AbstractBackgroundMitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combination with vemurafenib.Patients and methodsIn the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to participate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT).ResultsFive out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema.ConclusionsMultiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy.

scholarly journals Combined VEGFR and MAPK pathway inhibition in angiosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael J. Wagner ◽  
Yasmin A. Lyons ◽  
Jean H. Siedel ◽  
Robert Dood ◽  
Archana S. Nagaraja ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Combined Treatment ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
In Vivo Model ◽  
Mitogen Activated Protein

AbstractAngiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

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