Format

Send to

Choose Destination
Cancer Discov. 2015 Aug;5(8):832-41. doi: 10.1158/2159-8290.CD-14-1211.

HER2 activating mutations are targets for colorectal cancer treatment.

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
2
Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
3
Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
4
NSABP Foundation, Pittsburgh, Pennsylvania.
5
Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy. National Institute of Biostructures and Biosystems, Rome, Italy. rbose@dom.wustl.edu andrea.bertotti@ircc.it.
6
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. rbose@dom.wustl.edu andrea.bertotti@ircc.it.

Abstract

The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.

SIGNIFICANCE:

HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer.

PMID:
26243863
PMCID:
PMC4527087
DOI:
10.1158/2159-8290.CD-14-1211
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

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