Dataset Information

Imaging markers of response to combined BRAF and MEK inhibition in BRAF mutated vemurafenib-sensitive and resistant melanomas.

ABSTRACT: A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of magnetic resonance spectroscopy (1H-MRS) of choline and diffusion-weighted magnetic resonance imaging (DW-MRI) as early markers of response to BRAF inhibition (BRAFi) with vemurafenib alone or in combination with MEK inhibition (MEKi) with trametinib, in BRAFi-sensitive and BRAFi-resistant melanoma xenografts. Tumor response was significantly improved by the combination of BRAFi and MEKi, compared to BRAFi alone, only in sensitive xenografts; thus indicating that vemurafenib-resistant A375R xenografts were cross-resistant to the inhibition of MEK, as confirmed by immunohistochemistry analysis for phosphorylated ERK. In vivo1H-MRS showed that in sensitive melanoma xenografts, a significant blockage of ERK phosphorylation, but not a decrease in cell proliferation, was required to affect total choline (tCho) levels, thus suggesting that tCho could serve as a pharmacodynamic (PD) marker for agents targeting the MAPK cascade. In addition, early effects of the combination therapy on tumor cellularity could be detected via DW-MRI. In particular, skewness and kurtosis of the apparent diffusion coefficient (ADC) distribution may be useful to detect changes in the diffusional heterogeneity that might not affect the global ADC value.

SUBMITTER: Acciardo S

PROVIDER: S-EPMC5908289 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Imaging markers of response to combined BRAF and MEK inhibition in BRAF mutated vemurafenib-sensitive and resistant melanomas.

Acciardo Stefania S Mignion Lionel L Joudiou Nicolas N Bouzin Caroline C Baurain Jean-François JF Gallez Bernard B Jordan Bénédicte F BF

Oncotarget 20180330 24

A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of mag ...[more]

PMID: 29682188

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Project description:BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Project description:Primary and posttreatment resistance to BRAFV600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

Dataset Information

Imaging markers of response to combined BRAF and MEK inhibition in BRAF mutated vemurafenib-sensitive and resistant melanomas.

Publications

Imaging markers of response to combined BRAF and MEK inhibition in BRAF mutated vemurafenib-sensitive and resistant melanomas.

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