Uncovering the role of oncogenic
HER2
variants as drivers of pancreatic cancer.
Kanu, E; Sills, J; Shelley, R; Ginzel, J; Fernandes, J; Agritelley, E; Fletcher, A; Borowsky, AD; Shi, C; Cardiff, RD; Nussbaum, D; Allen, PJ ...
Published in: Journal of Clinical Oncology
The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) to conventional cytotoxic therapy underscores the need for advances in targeted molecular therapeutics. Previous studies have reported approximately 2% of PDAC patients with
gene amplification. While anti-
cancer therapy has yielded success in other disease sites, it has had minimal reported benefit in PDAC. Multiple
isoforms exist that are generated either by loss of exon 16 (
), or through N-terminal truncations (
). These isoforms are implicated in differential tumor behavior and response to anti-HER2 therapy in the breast but have not been investigated in PDAC. Herein, we hypothesize that these isoforms may underlie the observed resistance to
therapy in PDAC.
To test for the presence of HER2 structural variants within human PDAC, a tissue microarray was constructed of fifty-one primary tumor samples and two metastatic samples. Multiplex immunohistochemistry (mIHC) was performed for staining of the extracellular N-terminal and intracellular C-terminal HER2 domains. We then utilized our previously described
+ cancer rainbow (Crainbow) mouse model in which human wild-type
(
),
, and
were expressed in the same mouse along with fluorescent protein reporters.
Crainbow mice were crossed with PDX1-Cre recombinase to initiate recombination and expression of each fluorescently labelled
isoform during pancreas development. PDX1-Cre /
Crainbow mice were followed for up to one year and sacrificed to lineage trace each isoform and register
lineages with histopathology.
In our human data, four of fifty-three patient samples (three primary and one metastatic) had moderate-to-strong
staining. All samples identified on mIHC as
positive stained primarily for the
variant of
, with absence of the N-terminal domain and preservation of the intracellular domain. In our transgenic mice, 65% of the mouse cohort developed pre-malignant low grade pancreatic intraepithelial neoplasia (PanIN) by eight weeks. At one year, 58.3% of mice demonstrated advanced high grade PanIN, and 25% developed invasive disease. Lineage tracing revealed that while early low grade PanIN began as polyclonal lesions, comprised of
,
, and
expressing cells, advanced PanIN and invasive disease were unanimously monoclonal with one dominant isoform arising.
was represented abundantly in low grade disease, but high grade and invasive disease were predominantly driven by
and
Our data implicates the oncogenic
and
variants, rather than
, as the primary drivers of
PDAC tumorigenesis. In breast
has been described as a known cause of Trastuzumab resistance. Therefore, future efforts will be aimed at characterizing the mechanisms driving therapeutic resistance in
PDAC tumors.
