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

Andrea Aloia, Daniela Müllhaupt, Christophe D. Chabbert, Tanja Eberhart, Stefanie Flückiger-Mangual, Ana Vukolic, Ossia Eichhoff, Anja Irmisch, Leila T. Alexander, Ernesto Scibona, Dennie T. Frederick, Benchun Miao, Tian Tian, Chaoran Cheng, Lawrence N. Kwong, Zhi Wei, Ryan J. Sullivan, Genevieve M. Boland, Meenhard Herlyn, Keith T. FlahertyNicola Zamboni, Reinhard Dummer, Gao Zhang, Mitchell P. Levesque, Wilhelm Krek, Werner J. Kovacs

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 PPARa-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.

Original languageEnglish (US)
Pages (from-to)6852-6867
Number of pages16
JournalClinical Cancer Research
Volume25
Issue number22
DOIs
StatePublished - Nov 15 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors'. Together they form a unique fingerprint.

Cite this