Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies

Abstract

Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.

Keywords: HER2; cancer therapeutics; colorectal cancer; gastro/gastroesophageal cancer; resistance.

Figure 1

Select mechanisms of HER2 targeted resistance: (1) Acquired resistance to HER2 therapy involves compensatory activation of PI3K/AKT/mTOR and MAPK/ERK pathways, facilitated by various mechanisms such as MET amplification interacting with HGF [A], overexpression of HER2-family ligands (EGF, AREG, NRG1) [B], upregulation of phosphorylated IGF-1R [C], activation of Src-promoting signaling pathways [D], PTEN loss-of-function mutation causing PIP3 dysregulation [E], and co-amplifications of CDK6, CCND1, CCNE1 driving cell-cycle progression [F]. (2) The heterogeneous expression of HER2 in tumors contributes to primary and acquired resistance to HER2-targeted therapies. Progressive loss of HER2 positivity is a key factor in acquired resistance. Intratumoral heterogeneity is also common in gastric cancer, even before HER2 treatment (3) Mutations in HER2, together with HER2 and HER3 mutations, activate the PI3K–AKT pathway [G]. The generation of ERBB2d16 (HER2d16), a variant lacking exon 16′s extracellular domain, stabilizes homodimers and activates downstream signaling [H]. Overexpression of p95HER2 produces a truncated HER2 form without the extracellular domain [I] (4) Excessive mucin 4 (MUC4) expression and the CD44–polymeric hyaluronan complex can cause inhibition of Trastuzumab binding to HER2. Figure Abbreviations: AREG Amphiregulin; CCNE1 Cyclin E1 gene; CDK Cyclin; EGF/R Epidermal growth factor/receptor; FGFR3 Fibroblast growth factor receptor 3; HER1/2/3 Human epidermal growth factor rector 1/2/3; HGF Hepatocyte growth factor; IGF-1R Insulin-like growth factor 1 receptor; MET Mesenchymal epithelial transition; NRG1 Neuregulin 1; SRC Proto-oncogene tyrosine-protein kinase Src; PI3K/AKT phosphoinositide 3-kinase/AKT; PTEN phosphatase and tensin homolog; Ras/RAF/MEK/ERK Ras/Raf/MEK/extracellular signal-regulated kinase; Rb Retinoblastoma protein; RTK Receptor tyrosine kinase.