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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 BRAF^V600E -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 PPARα-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 BRAF^V600E -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 BRAF^V600E -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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