RT Journal Article
SR Electronic
T1 DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation of MITF
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101235
DO 10.26508/lsa.202101235
VO 5
IS 9
A1 Gutierrez-Prat, Nuria
A1 Zuberer, Hedwig L
A1 Mangano, Luca
A1 Karimaddini, Zahra
A1 Wolf, Luise
A1 Tyanova, Stefka
A1 Wellinger, Lisa C
A1 Marbach, Daniel
A1 Griesser, Vera
A1 Pettazzoni, Piergiorgio
A1 Bischoff, James R
A1 Rohle, Daniel
A1 Palladino, Chiara
A1 Vivanco, Igor
YR 2022
UL http://www.life-science-alliance.org/content/5/9/e202101235.abstract
AB MAPK inhibitors (MAPKi) remain an important component of the standard of care for metastatic melanoma. However, acquired resistance to these drugs limits their therapeutic benefit. Tumor cells can become refractory to MAPKi by reactivation of ERK. When this happens, tumors often become sensitive to drug withdrawal. This drug addiction phenotype results from the hyperactivation of the oncogenic pathway, a phenomenon commonly referred to as oncogene overdose. Several feedback mechanisms are involved in regulating ERK signaling. However, the genes that serve as gatekeepers of oncogene overdose in mutant melanoma remain unknown. Here, we demonstrate that depletion of the ERK phosphatase, DUSP4, leads to toxic levels of MAPK activation in both drug-naive and drug-resistant mutant melanoma cells. Importantly, ERK hyperactivation is associated with down-regulation of lineage-defining genes including MITF. Our results offer an alternative therapeutic strategy to treat mutant melanoma patients with acquired MAPKi resistance and those unable to tolerate MAPKi.