Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.
Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR.
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Daniele
D
Oddo
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Erin M
EM
Sennott
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Ludovic
L
Barault
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Emanuele
E
Valtorta
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Sabrina
S
Arena
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Andrea
A
Cassingena
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Genny
G
Filiciotto
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Giulia
G
Marzolla
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Elena
E
Elez
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Robin M J M
RM
van Geel
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Alice
A
Bartolini
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Giovanni
G
Crisafulli
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Valentina
V
Boscaro
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Jason T
JT
Godfrey
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Michela
M
Buscarino
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Carlotta
C
Cancelliere
Department of General Surgery, Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
Michael
M
Linnebacher
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Giorgio
G
Corti
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Mauro
M
Truini
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy.
Giulia
G
Siravegna
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Julieta
J
Grasselli
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Margherita
M
Gallicchio
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
René
R
Bernards
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Jan H M
JH
Schellens
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Josep
J
Tabernero
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Jeffrey A
JA
Engelman
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Andrea
A
Sartore-Bianchi
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
Alberto
A
Bardelli
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology, Università degli Studi di Milano, Milan, Italy.
Salvatore
S
Siena
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Ryan B
RB
Corcoran
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy. federica.dinicolantonio@unito.it.
Federica
F
Di Nicolantonio
D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction
D048493:Proto-Oncogene Proteins B-raf