Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases

Abstract

ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA. The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making.

Combined blockade of MEK and PI3KCA as an effective antitumor strategy in HER2 gene amplified human colorectal cancer models

“…With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, Owen et al reported the complete molecular characterization of these two cases of HER2 -amplified mCRC. Their findings included increased expression of MUC1 and MET , decreased expression of PTEN , and an activating mutation in PIK3CA [46]. These data support the hypothesis that a potentially promising alterative to overcome resistance mechanisms would be to apply a therapy in the upfront setting in order to suppress and ideally eradicate pre-existing resistant clones while they still are present in a low frequency subpopulation.…”

Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer

“…Although HER2 blockade was remarkably effective, especially considering that the patients had received a median of five prior lines of treatment, most cases eventually relapsed, with a median progression-free survival (PFS) of 21 weeks (Sartore-Bianchi et al, 2016). How ERBB2-amplified gastrointestinal tumors that initially respond to HER2 blockade evolve during therapy and become resistant is largely unknown (Kim et al, 2018;Owen et al, 2018). Further knowledge is key to devising additional lines of treatment or mounting combinatorial preventive strategies.…”

Targeting of fluorescent Lactococcus lactis to colorectal cancer cells through surface display of tumour‐antigen binding proteins

“…This might be due to greater expression of the EpCAM tumour antigen in these cells, compared to HER2; however, this cannot be directly compared in this study due to the use of different antibodies. It was previously reported that in CRC EpCAM expression was up‐regulated by 100‐fold to 1000‐fold (Seeber et al ., 2016), while HER2 expression was up‐regulated by fivefold (Owen et al ., 2018) and 12‐fold (Blok et al ., 2013). Nevertheless, HER2 overexpression has been shown in patients with CRC (Ross and McKenna, 2001), and it has been suggested as a promising alternative therapeutic target (Ingold Heppner et al ., 2014; Greally et al ., 2018; Ross et al ., 2018).…”