Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression.

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.

A Novel HER3-Targeting Antibody-Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization.

PURPOSE: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models. EXPERIMENTAL DESIGN: In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patient-derived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys. RESULTS: U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3-activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys. CONCLUSIONS: U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3-mediated payload delivery via high internalization into tumor cells.

Asialoglycoprotein receptor promotes cancer metastasis by activating the EGFR-ERK pathway.

Although the importance of glycans in malignant cell behavior is well documented, the potential involvement of endogenous lectins as modifiers of progression and metastasis in the tumor microenvironment has not been explored. In this study, we show that loss of the hepatic asialoglycoprotein receptor (ASGPR) in mice severely reduces the frequency of spontaneous lung metastasis after intrahepatic implantation of murine Lewis lung carcinoma (3LL) cells. Conversely, in vitro treatment with recombinant ASGPR increased the invasive and metastatic capacity of 3LL cells before intrahepatic implantation. ASGPR treatment in vitro increased the expression and production of matrix metalloproteinase-9 through activation of the epidermal growth factor receptor-extracellular signal-regulated kinase (EGFR-ERK) pathway. Our findings identify ASGPR as a novel important factor that responds to endogenous lectins in the tumor microenvironment to promote cancer metastasis by activating the EGFR-ERK pathway through interactions with counter-receptors on cancer cells.

A galectin-3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells.

BACKGROUND: A common polymorphism, rs4644, coding for Pro64 or His64 of the carbohydrate-binding protein galectin-3, influences the susceptibility of galectin-3 to cleavage by matrix metalloproteinases and is associated with breast cancer incidence. Because forced expression of galectin-3 in a galectin-3 null breast cancer cell line confers sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the authors sought to determine whether the His64/Pro64 polymorphism of galectin-3 affects the sensitivity to TRAIL. METHODS: Genomic DNA of breast cell lines was analyzed for the single nucleotide polymorphism rs4644, and cytotoxicity was determined with the MTT assay. RESULTS: When a collection of 9 breast cancer cell lines that express galectin-3 was examined for lectin, galactoside-binding, soluble, 3 (LGALS3) genotype and sensitivity to doxorubicin and TRAIL, doxorubicin sensitivity was not found to be related to LGALS3 genotype. In contrast, none of the 5 cell lines that were homozygous for Pro64 galectin-3 were found to be sensitive to TRAIL, but 2 of 2 homozygous His64 cell lines and 1 of 2 heterozygous His64 cell lines were sensitive to TRAIL. Forced expression of galectin-3 of defined genotype in galectin-3 null cells was used to more directly test the effect of the Pro64His mutation on TRAIL sensitivity. High levels of expression of His64 galectin-3 rendered BT549 cells sensitive to TRAIL and resistant to doxorubicin, but cells expressing Pro64 galectin-3 remained resistant to TRAIL and sensitive to doxorubicin. CONCLUSIONS: The results of the current study indicate that the naturally occurring Pro64His mutation in galectin-3 increases sensitivity to death receptor-mediated apoptosis. This finding could be relevant to disparities in breast cancer outcomes across population groups, and could guide the design of future clinical trials of TRAIL-based therapies.

Potentiation of proliferation of some but not all human colon carcinoma cell lines by immobilized hepatic asialoglycoprotein receptor 1.

Twenty-three human colorectal carcinoma cell lines were examined for the binding of recombinant hepatic asialoglycoprotein receptor 1 (ASGR1), which is known to be exclusively expressed on hepatic parenchymal cells. The effects of the binding were assessed by adhesion to and proliferation on immobilized recombinant ASGR1. Recombinant ASGR1 bound strongly to six cell lines and moderately to 15 cell lines out of 23 lines tested, as shown by flow cytometric analysis. The first six cell lines (group A) also exhibited strong adherence to immobilized ASGR1, whereas 11 of the 15 cell lines of the second group (group B) showed significant adhesion with smaller enhancement by ASGR1 than the cell lines in group A. With a representative cell line (DLD-1 cells categorized in group B), a significant portion of the adhesion was inhibited by preincubation of ASGR1 with asialofetuin, a competitive inhibitor of the carbohydrate recognition by ASGR1. The growth rates of 13 cell lines (two of group A and 11 of group B) were significantly accelerated when they were cultured on immobilized recombinant ASGR1. The results indicate that ASGR is a potential organ-specific microenvironmental factor for colorectal carcinoma growth and metastasis formation in livers.