MAPK Pathway–Targeted Therapies: Care and Management of Unique Toxicities in Patients With Advanced Melanoma

Rubin, Krista M.

doi:10.1188/17.cjon.699-709

Cited by 15 publications

(10 citation statements)

References 46 publications

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“…The grey square corresponds to patients who received cardiotropic treatments, whereas the grey circle represents patients who did not of BRAF and MEKis. [8][9][10] In the present study, 3 patients (3.4%) presented a decline in LVEF ≥10% to a value <50% (data not shown). This frequency is consistent with that reported in clinical trials.…”

Section: Discussionmentioning

confidence: 39%

“…No patient was treated with the combination of encorafenib-binimetinib. The median duration of treatment was 9 months (IQR [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]). 30 patients (34.1%) had a rechallenge after progressive disease under previous treatment with BRAF and/or MEKis.…”

Section: Baseline Characteristics Of Study Populationmentioning

confidence: 99%

“…8 months (IQR [6][7][8][9]) for patients whose BRAF and/or MEKis were discontinued, and 7 months (IQR [6][7][8][9][10][11][12][13][14][15][16]) for the others. All patients who benefited from a specific treatment had a normalization of LVEF at the end of follow-up.…”

Section: Management Of Patients With Lvef-dmentioning

confidence: 99%

“…6,7 LVEF-D induced by BRAF and MEKis, although widely reported in clinical trials, has never been thoroughly described to date and data regarding its management are limited. [8][9][10] The main objective of the study presented herein was therefore to describe the characteristics of LVEF-D in a large cohort of metastatic melanoma patients treated with BRAF and/or MEKis in a real-life setting. Secondary objectives were to determine whether laboratory, electrocardiogram (ECG) or transthoracic echocardiography (TTE) markers could identify sub-clinical cardiac damage and be predictive of a LVEF-D.…”

Section: Introductionmentioning

confidence: 99%

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Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

et al. 2020

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BRAF and MEKis have revolutionized the management of BRAF V600 -mutated melanoma patients. Left ventricular ejection fraction decrease (LVEF-D) related to these treatments has not been thoroughly evaluated to date. The main objective of this study was to describe characteristics of LVEF-D in melanoma patients treated with BRAF and/or MEKis. Metastatic melanoma patients treated with BRAF and/ or MEKis between March 1, 2012 and May 18, 2018 were included retrospectively (Lyon Sud University Hospital, Hospices Civils de Lyon). LVEF-D was defined as a reduction in LVEF ≥10% from baseline to a value <55%; normalization was defined as a value ≥55%. Among the 88 patients included, 12 (13.6%) experienced a LVEF-D, including 10 grade 2 and 2 grade 3. The median onset of which was 11 months (IQR [3-21]). No patient previously treated with beta-blockers (n = 12) experienced a LVEF-D. Analysis of laboratory parameters, electrocardiogram, and transthoracic echocardiography during the follow-up did not find any predictive marker of LVEF-D. All patients who benefited from a specific treatment of LVEF-D had a normalization of LVEF at the end of follow-up. LVEF recovery was significantly better for patients treated with angiotensin converting enzyme inhibitors and beta-blockers than those who did not (P = .019). Ophthalmological adverse events were significantly more frequent in patients who experienced a LVEF-D (P = .006) and the latter did not influence overall-survival (P = .117) or progression-free-survival (P = .297). LVEF-D is a common and easily manageable adverse event due to BRAF and MEKis. Its association with ocular toxicity suggests a close ophthalmological monitoring when LVEF-D occurs. K E Y W O R D Sadverse events, BRAF inhibitor, cardiac toxicity, heart failure, left ventricular ejection fraction, left ventricular systolic dysfunction, MEK inhibitor, metastatic melanoma 2612 | BERGER Et al.

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Section: Discussionmentioning

confidence: 39%

Section: Baseline Characteristics Of Study Populationmentioning

confidence: 99%

Section: Management Of Patients With Lvef-dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

et al. 2020

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“…In vivo studies in mice have demonstrated that a disruption of certain growth factors inputs, including those of VEGF and fibroblast growth factors (FGFs), results in reduction of ERK signaling and the loss of vascular integrity and vessel involution ( Lee et al, 2007 ; Murakami et al, 2008 ). At the same time, clinical uses of drugs targeting VEGF, such as bevacizumab, or the downstream signaling pathway, such as the mitogen-activated kinase (MEK) inhibitor trametinib, are associated with extensive and poorly understood cardiovascular side effects, including hemorrhage and hypertension ( Porta et al, 2015 ; Banks et al, 2017 ; Rubin, 2017 ). These observations notwithstanding, the role of ERK signaling and specific ERK isoforms in these events is unknown.…”

Section: Introductionmentioning

confidence: 99%

Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

Ricard

Scott

Booth

et al. 2019

Journal of Experimental Medicine

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To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

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Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

et al. 2021

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Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/ Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low

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MAPK Pathway–Targeted Therapies: Care and Management of Unique Toxicities in Patients With Advanced Melanoma

Cited by 15 publications

References 46 publications

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

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