SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy

A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.

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Role of Mitogen-Activated Protein Kinase Pathway in Prostaglandin F2α-Induced Rat Puerperal Uterine Contraction

Endocrinology ◽

10.1210/endo.138.8.5305 ◽

1997 ◽

Vol 138 (8) ◽

pp. 3103-3111 ◽

Cited By ~ 31

Author(s):

Masahide Ohmichi ◽

Koji Koike ◽

Akiko Kimura ◽

Kanji Masuhara ◽

Hiromasa Ikegami ◽

...

Keyword(s):

Map Kinase ◽

Uterine Contraction ◽

Prostaglandin F2α ◽

Mek Inhibitor ◽

Biological Action ◽

Mitogen Activated Protein Kinase ◽

Myometrial Cells ◽

Mitogen Activated Protein ◽

Kinase Pathway

Abstract In this study, prostaglandin (PG) F2α was found to activate mitogen-activated protein (MAP) kinase and MAP kinase kinase (MEK) in cultured rat puerperal uterine myometrial cells. PGF2α stimulation also led to an increase in phosphorylation of raf-1, son of sevenless (SOS), and Shc. Furthermore, we examined the mechanism by which PGF2α induced MAP kinase phosphorylation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the β-adrenergic receptor kinase 1 (βARK1), which specifically blocks signaling mediated by the βγ subunits of G proteins, blocked the PGF2α-induced activation of MAP kinase. Ritodrine (1 μm), which is known to relax uterine muscle contraction, attenuated PGF2α-induced tyrosine phosphorylation of MAP kinase. Moreover, to examine the role of MAP kinase pathway in uterine contraction, an inhibitor of MEK activity, PD098059, was used. Although MEK inhibitor had no effect on PGF2α-induced calcium mobilization, this inhibitor partially inhibited PGF2α-induced uterine contraction. These results provide evidence that PGF2α stimulates the MAP kinase signaling pathway in cultured rat puerperal uterine myometrial cells through Gβγ protein, suggesting that this new pathway may play an important role in the biological action of PGF2α on these cells.

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Loss of Wild-Type Kras is Associated with Enhanced Fitness and Increased Mitogen-Activated Protein Kinase Pathway Addiction in K-RasG12D Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.907.907 ◽

2014 ◽

Vol 124 (21) ◽

pp. 907-907

Author(s):

Michael R. Burgess ◽

Eugene Hwang ◽

Anica M. Wandler ◽

Saurabh Asthana ◽

Elizabeth M. Davis ◽

...

Keyword(s):

Protein Kinase ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Resistant Clone ◽

Wild Type ◽

Retroviral Integration ◽

Enhanced Sensitivity ◽

Mitogen Activated Protein ◽

Kinase Pathway ◽

Acute Myeloid

Abstract Functional analysis of therapeutic outlier responses in cancer therapy can identify unexpected synthetic lethal interactions and uncover biomarkers that predict enhanced sensitivity to targeted agents. We performed preclinical trials of the MEK inhibitor PD0325901 (PD901) in primary murine acute myeloid leukemias (AMLs) generated using retroviral insertional mutagenesis in KrasG12D “knock-in” mice. Similar to previous observations Nf1 and Nras mutant leukemias, treatment with PD901 prolonged survival in six independent leukemias harboring diverse retroviral integrations. Intriguingly, one outlier leukemia, clone Kras.101, demonstrated a greater than 4-fold improvement in median overall survival when treated with the MEK inhibitor. Importantly, this AML demonstrated a novel retroviral integration at relapse, indicating clonal evolution during treatment. The relapsed clone displayed phenotypic resistance upon transplantation into secondary recipients and retreatment with PD901. We performed a detailed analysis of the paired PD901-sensitive/resistant Kras.101 clones to identify the mediators of mitogen-activated protein kinase pathway (MAPK) addiction. Functional studies demonstrated that the novel dominant retroviral integration in the PD901 resistant clone did not directly alter drug response. However, genome-wide analysis of copy number alterations revealed a gain of chromosome 6 involving the Kras locus in the resistant clone, which was confirmed by spectral karyotyping and fluorescence in situ hybridization. Surprisingly, the PD901-sensitive leukemia harbored two copies of oncogenic KrasG12D due to somatic uniparental disomy, while the resistant clone harbored two mutant and one wild-type Kras alleles. This observation and paired single nucleotide polymorphism analysis indicated that the PD901-resistant leukemia was evolutionarily ancestral to the drug sensitive clone. Consistent with this hypothesis, competitive repopulation experiments with fluorescently labeled leukemia cells demonstrated increased fitness of the drug sensitive leukemia in the absence of the MEK inhibitor and over-expression of wild type K-Ras in the drug-sensitive leukemia reduced fitness in vivo. Finally, utilizing a tetracycline-inducible system, we found that wild-type Kras expression enhances the fitness of the Kras.101 clone only in the presence of the MEK inhibitor. Together, these data suggest that loss of wild-type Kras imparts a fitness advantage at the expense of increased MAPK pathway addiction, which results in enhanced sensitivity to MEK inhibition in leukemias driven by oncogenic K-Ras. Disclosures No relevant conflicts of interest to declare.

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Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2015.62.4726 ◽

2015 ◽

Vol 33 (34) ◽

pp. 4099-4105 ◽

Cited By ~ 65

Author(s):

Rachel N. Grisham ◽

Brooke E. Sylvester ◽

Helen Won ◽

Gregory McDermott ◽

Deborah DeLair ◽

...

Keyword(s):

Ovarian Cancer ◽

Functional Characterization ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Low Grade ◽

Outlier Analysis ◽

Pathway Activation ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Kinase Pathway

Purpose No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. Patients and Methods Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. Results Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor–based combination therapy. Conclusion Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.

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A Case of Non-Resolving MEK Inhibitor-Associated Retinopathy

Case Reports in Ophthalmology ◽

10.1159/000503414 ◽

2019 ◽

Vol 10 (3) ◽

pp. 334-338

Author(s):

John R. Chancellor ◽

David A. Kilgore ◽

Ahmed B. Sallam ◽

Richard C. Allen ◽

Sami H. Uwaydat

Keyword(s):

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Drug Discontinuation ◽

Serous Fluid ◽

Factor Inhibitor ◽

Mitogen Activated Protein ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Kinase Pathway ◽

Stimulating Factor

The mitogen-activated kinase pathway plays an important role in cell survival, and its dysregulation is associated with cancers such as melanoma. Drugs designed to target this pathway have been associated with serous retinal detachments in a new entity termed MEK inhibitor-associated retinopathy (MEKAR). MEKAR has classically been described as self-limiting, with serous fluid often resolving without discontinuation of the drug. We present a case in which a patient undergoing treatment for metastatic melanoma with lacnotuzumab, a macrophage colony-stimulating factor inhibitor that blocks an upstream component of the mitogen-activated protein kinase pathway, developed serous retinopathy that did not resolve despite drug discontinuation.

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1333: Proteinase-Activated Receptor-2 Activation of the Mitogen Activated Protein Kinase Pathway in Human Cultured Prostate Stromal Cells

The Journal of Urology ◽

10.1016/s0022-5347(18)38558-6 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 351-351

Author(s):

Andrew Myatt ◽

Duncan R. Harriss ◽

Stephen J. Hill

Keyword(s):

Protein Kinase ◽

Stromal Cells ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Kinase Pathway

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Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽

10.1530/reprod/120.2.377 ◽

2000 ◽

pp. 377-383 ◽

Cited By ~ 13

Author(s):

L Leonardsen ◽

A Wiersma ◽

M Baltsen ◽

AG Byskov ◽

CY Andersen

Keyword(s):

Signal Transduction ◽

Protein Kinase ◽

Protein Kinase A ◽

Mitogen Activated Protein Kinase ◽

Meiotic Maturation ◽

Mouse Oocytes ◽

Mitogen Activated Protein ◽

Dependent Signal ◽

Kinase Pathway ◽

Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

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