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A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors.

ABSTRACT: PURPOSE:Treatment of BRAFV600E -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi. EXPERIMENTAL DESIGN:By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens. RESULTS:Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPAR?-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E -mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo. CONCLUSIONS:Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E -mutant melanoma.

SUBMITTER: Aloia A

PROVIDER: S-EPMC6906212 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of <i>BRAF</i>-mutated Melanoma to MAPK Inhibitors.

Aloia Andrea A Müllhaupt Daniela D Chabbert Christophe D CD Eberhart Tanja T Flückiger-Mangual Stefanie S Vukolic Ana A Eichhoff Ossia O Irmisch Anja A Alexander Leila T LT Scibona Ernesto E Frederick Dennie T DT Miao Benchun B Tian Tian T Cheng Chaoran C Kwong Lawrence N LN Wei Zhi Z Sullivan Ryan J RJ Boland Genevieve M GM Herlyn Meenhard M Flaherty Keith T KT Zamboni Nicola N Dummer Reinhard R Zhang Gao G Levesque Mitchell P MP Krek Wilhelm W Kovacs Werner J WJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20190802 22

<h4>Purpose</h4>Treatment of <i>BRAF<sup>V600E</sup></i> -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.<h4>Experimental design</h4>By screening proteins expressed on the cell surface of melanoma cells, we i ...[more]

PMID: 31375515

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Project description:BackgroundMost mutations in melanoma affect one critical amino acid on BRAF gene, resulting in the V600E substitution. Patient management is often based on the use of specific inhibitors targeting this mutation.MethodsDNA and RNA mutation status was assessed in 15 melanoma cell lines by Sanger sequencing and RNA-seq. We tested the cell lines responsiveness to BRAF inhibitors (vemurafenib and PLX4720, BRAF-specific and sorafenib, BRAF non-specific). Cell proliferation was assessed by MTT colorimetric assay. BRAF V600E RNA expression was assessed by qPCR. Expression level of phosphorylated-ERK protein was assessed by Western Blotting as marker of BRAF activation.ResultsThree cell lines were discordant in the mutation detection (BRAF V600E at DNA level/Sanger sequencing and BRAF WT on RNA-seq). We initially postulated that those cell lines may express only the WT allele at the RNA level although mutated at the DNA level. A more careful analysis showed that they express low level of BRAF RNA and the expression may be in favor of the WT allele. We tested whether the discordant cell lines responded differently to BRAF-specific inhibitors. Their proliferation rate decreased after treatment with vemurafenib and PLX4720 but was not affected by sorafenib, suggesting a BRAF V600E biological behavior. Yet, responsiveness to the BRAF specific inhibitors was lower as compared to the control. Western Blot analysis revealed a decreased expression of p-ERK protein in the BRAF V600E control cell line and in the discordant cell lines upon treatment with BRAF-specific inhibitors. The discordant cell lines showed a lower responsiveness to BRAF inhibitors when compared to the BRAF V600E control cell line. The results obtained from the inhibition experiment and molecular analyses were also confirmed in three additional cell lines.ConclusionCell lines carrying V600E mutation at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.

Dataset Information

A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors.

Publications

A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of <i>BRAF</i>-mutated Melanoma to MAPK Inhibitors.

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