An HER3-targeting antibody–drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small
cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance.
U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor,
DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant
NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant
clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination
with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells
using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402
induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X,
a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found
using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells
was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased
in resistant cells. In addition, administration of U3-1402 notably repressed growth
of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells
expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using
immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9
cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates
that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload
cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate
that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential
as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
The human epidermal growth factor receptor (HER) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response to extracellular ligands, regulating diverse processes that include differentiation, migration, proliferation, and survival. Alterations in these genes play a role in the development and progression of many human cancers. In gastric carcinomas (GCs), expression of HER1 and HER2 is thought to be a prognostic factor and target of novel biologic agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. In this study, we explored the gene and protein expression of the HER family in GC to establish new potential prognostic factors. Immunohistochemistry and fluorescence in situ hybridization were performed in 221 patients with GC using tissue microarray. Correlation between the expression or amplification of HER genes and the clinicopathologic parameters was statistically analyzed. Alterations of members of the HER family were significantly associated with the parameters involved in tumor progression, including depth of tumor invasion, involved lymph nodes, and tumor stage. In addition, HER2 amplification and HER3 expression were significantly related to worse survival. These results reveal that all members of the HER family are expressed in GC. Furthermore, expression of HER2 and HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER-targeted agents and agents targeting downstream signaling pathways provides new possibilities in the treatment of GC.
Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). The differences in intracellular signaling networks between gefitinib-sensitive and -resistant NSCLCs remain poorly understood. In this study, we observe that gefitinib reduces phospho-Akt levels only in NSCLC cell lines in which it inhibits growth. To elucidate the mechanism underlying this observation, we compared immunoprecipitates of phosphoinositide 3-kinase (PI3K) between gefitinib-sensitive and -resistant NSCLC cell lines. We observe that PI3K associates with ErbB-3 exclusively in gefitinib-sensitive NSCLC cell lines. Gefitinib dissociates this complex, thereby linking EGFR inhibition to decreased Akt activity. In contrast, gefitinib-resistant cells do not use ErbB-3 to activate the PI3K/Akt pathway. In fact, abundant ErbB-3 expression is detected only in gefitinib-sensitive NSCLC cell lines. Two gefitinib-sensitive NSCLC cell lines with endogenous distinct activating EGFR mutations (L858R and Del747-749), frequently observed in NSCLC patients who respond to gefitinib, also use ErbB-3 to couple to PI3K. Down-regulation of ErbB-3 by means of short hairpin RNA leads to decreased phospho-Akt levels in the gefitinib-sensitive NSCLC cell lines, Calu-3 (WT EGFR) and H3255 (L858R EGFR), but has no effect on Akt activation in the gefitinib-resistant cell lines, A549 and H522. We conclude that ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.