Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

Han, Chanhee; Bellone, Stefania; Zammataro, Luca; Schwartz, Peter E.; Santin, Alessandro D.

doi:10.1016/j.gore.2018.05.011

Cited by 23 publications

(12 citation statements)

References 12 publications

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“…It is important to note that tumor samples were not available for testing in 35% of the patients (18 of 52) in this study. In agreement with our results, two recent case reports on LGSC patients with remarkable and durable clinical responses (> 5 years) to MEKi therapy have reported oncogenic KRAS mutations (both G12V) in their tumors [23, 47]. As LGSC is often an indolent disease, the inclusion of patients with stable disease should also be considered in the future evaluation of RAS mutation status as a predictive biomarker.…”

Section: Discussionsupporting

confidence: 91%

“…While these responses were limited, response rates using conventional chemotherapy in patients with relapsed LGSC are disappointingly low (4%) [45]. More recently, a number of LGSC cases have been reported, highlighting dramatic and durable responses to MEKi treatment [22, 23, 46, 47]. Currently, there are no predictive biomarkers of MEKi response for LGSC.…”

Section: Discussionmentioning

confidence: 99%

“…A second clinical trial of the MEKi binimetinib (MILO trial, NCT01849874) was closed at the interim analysis in 2016, because it did not show the anticipated predefined benefits on progression-free survival (PFS). Despite these unexpected results, durable responses to binimetinib were observed in LGSC with MAPK pathway alterations [23]. Currently, an international randomized phase II/III clinical trial using the MEKi trametinib is ongoing (NCT02101788) and a translational research component to better understand the molecular mechanisms of MEKi efficacy is included.…”

Section: Introductionmentioning

confidence: 99%

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Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

et al. 2019

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BackgroundAlthough low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed.MethodsWe evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays.ResultsLow-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested.ConclusionsKRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0725-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

et al. 2019

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“…In contrast, MAPK inhibition produced nuclear migration of VDR and decreased cell viability in vitro. Inhibition of the MAPK pathway in EOC has been considered as a potential approach in subgroups of patients with specific histologic profiles, especially low-grade histology, although targeted therapies have so far failed to exhibit reliable therapeutic effects (Farley et al 2013;Han et al 2018;Fernandez et al 2019). Thus defining subgroups of suitable patients for MAPK inhibition remains highly important.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic VDR expression as an independent risk factor for ovarian cancer

Czogalla

Deuster

Liao

et al. 2020

Histochem Cell Biol

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The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high-and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013; Cc = 0.203), positive lymph node status (p = 0.023; Cc = 0.236), high-grade serous histology (p = 0.000; Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006; Cc = − 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached; p < 0.001) and was confirmed as a statistically independent prognostic factor in the Cox regression multivariate analysis. Additional knowledge of VDR as a biomarker and its interactions within the mitogen-activated protein kinase (MAPK) signaling pathway could potentially improve the prognosis of therapeutic approaches for specific subgroups in EOC.

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“…In recent clinical trial with LGSOC patients, KRAS mutation were found to be associated with better response to MEK inhibition with significant improvement in PFS with binimetinib when compared to physician choice of chemotherapy [67]. Other single case reports have shown similar findings [68,69]. While promising results of MEKi therapy for the treatment of LGSOC patients have been demonstrated in recent studies [70,71], biomarkers that predict treatment efficacy are largely unknown.…”

Section: Discussionmentioning

confidence: 92%

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

Shrestha

Fernández

Dawson

et al. 2020

Preprint

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Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates. As such, there is a pressing need to develop more effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use a multiomics approach to interrogate a collection of LGSOC patient-derived cell lines to elucidate novel biomarkers and therapeutic vulnerabilities.Methods: Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches.LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets. Results: KRAS mutations were exclusively found in MEKi-sensitive and NRAS mutations mostly in MEKiresistant cell lines. Analysis of COSMIC mutational signatures revealed distinct patterns of nucleotide substitution mutations in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes (chromosome 9p21) were much more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. For in-vitro MEKi efficacy prediction, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines.Conclusions: Our LGSOC cell lines are representative models of the most common molecular aberrations found in LGSOC tumors. This study highlights the importance of using proteomic data in multiomics assessment of drug prediction and identification of potential therapeutic targets. CDKN2A/B and MTAP deficiency offer an opportunity to find synthetically lethal candidates for novel treatments.Multiomics approaches are crucial to improving our understanding of the molecular aberrations inLGSOC, establishing effective drug prediction programs and identifying novel therapeutic targets inLGSOC. BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer with a poor prognosis. Women with LGSOC are usually diagnosed with advanced-stage disease and only 10-20% are alive 10 years after diagnosis [1,2]. Research on LGSOC is challenging due to its low prevalence, uncertain etiology, and the limited availability of research models. However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutatio...

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Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

Cited by 23 publications

References 12 publications

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

Cytoplasmic VDR expression as an independent risk factor for ovarian cancer

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

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