A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors
Document Type
Article
Publication Date
11-15-2019
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.
Identifier
85075101626 (Scopus)
Publication Title
Clinical Cancer Research
External Full Text Location
https://doi.org/10.1158/1078-0432.CCR-19-0253
e-ISSN
15573265
ISSN
10780432
PubMed ID
31375515
First Page
6852
Last Page
6867
Issue
22
Volume
25
Grant
P01 CA114046
Fund Ref
National Institutes of Health
Recommended Citation
Aloia, Andrea; Müllhaupt, Daniela; Chabbert, Christophe D.; Eberhart, Tanja; Flückiger-Mangual, Stefanie; Vukolic, Ana; Eichhoff, Ossia; Irmisch, Anja; Alexander, Leila T.; Scibona, Ernesto; Frederick, Dennie T.; Miao, Benchun; Tian, Tian; Cheng, Chaoran; Kwong, Lawrence N.; Wei, Zhi; Sullivan, Ryan J.; Boland, Genevieve M.; and Herlyn, Meenhard, "A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors" (2019). Faculty Publications. 7190.
https://digitalcommons.njit.edu/fac_pubs/7190
