Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma.
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jvillanueva@wistar.org.
Jessie
J
Villanueva
Jeffrey R
JR
Infante
Clemens
C
Krepler
Patricia
P
Reyes-Uribe
Minu
M
Samanta
Hsin-Yi
HY
Chen
Bin
B
Li
Rolf K
RK
Swoboda
Melissa
M
Wilson
Adina
A
Vultur
Mizuho
M
Fukunaba-Kalabis
Bradley
B
Wubbenhorst
Thomas Y
TY
Chen
Qin
Q
Liu
Katrin
K
Sproesser
Douglas J
DJ
DeMarini
Tona M
TM
Gilmer
Anne-Marie
AM
Martin
Ronen
R
Marmorstein
David C
DC
Schultz
David W
DW
Speicher
Giorgos C
GC
Karakousis
Wei
W
Xu
Ravi K
RK
Amaravadi
Xiaowei
X
Xu
Lynn M
LM
Schuchter
Meenhard
M
Herlyn
Katherine L
KL
Nathanson
D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048370:MAP Kinase Kinase 2