Format

Send to

Choose Destination
Cancer Res. 2016 Aug 1;76(15):4504-15. doi: 10.1158/0008-5472.CAN-16-0396. Epub 2016 Jun 16.

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

Author information

1
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
2
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
3
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
4
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
5
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
7
Department of Drug Science and Technology, University of Turin, Turin, Italy.
8
Department of General Surgery, Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
9
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.
10
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
11
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology, Università degli Studi di Milano, Milan, Italy.
12
Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy. federica.dinicolantonio@unito.it.

Abstract

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.

PMID:
27312529
PMCID:
PMC4970882
DOI:
10.1158/0008-5472.CAN-16-0396
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center