BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact.
OBJECTIVE
Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.


METHODS
Fifty-nine BRAF(V600)-mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.


RESULTS
Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.


CONCLUSIONS
Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required.
Authors' Affiliations: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute; Departments of Medical Oncology and Surgical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead; Melanoma Institute Australia; Disciplines of Pathology, Medicine, and Surgery, Sydney Medical School, The University of Sydney, Sydney; Departments of Melanoma and Surgical Oncology and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Helen
H
Rizos
Alexander M
AM
Menzies
Gulietta M
GM
Pupo
Matteo S
MS
Carlino
Carina
C
Fung
Jessica
J
Hyman
Lauren E
LE
Haydu
Branka
B
Mijatov
Therese M
TM
Becker
Suzanah C
SC
Boyd
Julie
J
Howle
Robyn
R
Saw
John F
JF
Thompson
Richard F
RF
Kefford
Richard A
RA
Scolyer
Georgina V
GV
Long
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010091:Oximes / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib