Targeting ErbB3 Research Articles

Synthesis, Characterization, in Silico and in vitro Screening of Anticancer Activity of Novel Curcumin Analogues

Global problem of cancer associated side effects with current chemotherapeutics and promising anticancer activity of curcumins, intended present study to carry out the synthesis of some new curcumin analogues using chromone aldehydes and cyclic ketones. The study involved in silico screening and in vitro anticancer evaluation of new synthesized compounds against the breast cancer cell line MDA-MB-231 using the MTT assay. All synthesized compounds exhibited significant cytotoxicity, with IC50 values ranging from 34.04 ± 0.05 µg to 43.96 ± 0.05 µg, comparable to the standard drug cisplatin (IC50 = 29.25 ± 0.14 µg). Among all new synthesized curcumin analogues, compound 2 exhibited the highest anticancer activity. Molecular docking studies supported these findings, demonstrating strong binding affinities of the chromone compounds to key protein targets EGFR (PDB ID: 3UG2) and ERBB2 (PDB ID: 3H3B), critical in breast cancer pathogenesis. The strong cytotoxic effects and binding affinities suggest that curcumin analogues could serve as promising candidates for developing targeted anticancer therapies.

ERBB2 Targeting Reveals a Significant Suppression of Tumorigenesis in Murine Endometrial Cancer with Pten Mutation.

Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgrcre/+Erbb2f/fPtenf/f (Erbb2d/d Ptend/d) was developed to evaluate the effect of ERBB2 targeted therapy in endometrial cancer with PTEN deficiency. Histopathological and molecular analysis was performed for Ptend/d and Erbb2d/dPtend/d mice. Histopathological analysis revealed that Erbb2d/dPtend/d mice significantly reduced development and progression of endometrial cancer compared to Ptend/d mice. Furthermore, percentage of proliferative cells in Erbb2d/dPtend/d mice revealed anti-tumorigenic effect of Erbb2 ablation compared to Ptend/d mice. Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Ptend/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Ptend/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.

Abstract LB450: Mechanisms of acquired resistance to AKT inhibitor capivasertib in AKT1 mutant patient derived breast cancer models

Abstract Capivasertib, a pan-AKT inhibitor, has recently been approved in combination with fulvestrant to treat ER+ HER2- breast cancer patients with one or more of PI3KCA/AKT1/PTEN alterations. However, as with many targeted therapies acquired drug resistance remains a challenge. In this study, we investigated the mechanisms of acquired capivasertib resistance in AKT1 mutant breast cancer models. We established two estrogen receptor positive (ER+) AKT1 E17K mutant breast cancer patient derived organoids (PDOs), that were sensitive to capivasertib in vitro. PDOs were chronically exposed to 1µM capivasertib. PDOs were sequenced (DNA & RNA) at multiple timepoints of treatment (3 days, 4 and 9 weeks after development of resistance). Using CRISPR-Cas9 editing we also engineered CAMA1 (ER+) cells to express AKT1 E17K, and generated derived resistant AKT1 mutant and parental models in response to continuous capivasertib exposure. CAMA1 AKT1 mutant and parental resistant were screened with an siRNA Kinome library supplemented with genes from the PDO RNA-sequencing. Phosphoproteomics was performed on capivasertib resistant E17K models in the presence and absence of capivasertib. PDO models persisting after either 4 or 9 weeks of capivasertib treatment showed no acquisition of genetic driver events, or changes in AKT copy number. Resistant organoids at 9 weeks treatment showed increased expression of ERBB3 (HER3), EGFR3 and LPAR5 as well as increased expression of MAPK signalling components. In siRNA screens on CAMA1 derived resistant models, siRNA targeting ERBB2, CDK4, PLK4 and CHEK1, ESR1 and LPAR5 modulated sensitivity to capivasertib. Analysis of phosphoproteins in capivasertib resistant models revealed reactivation of mTORC1 signalling despite sustained AKT inhibition, with dramatic upregulation of PDK1 and mTORC2. Consistent with the siRNA screens, drug combinations identified fulvestrant as a synergistic agent with capivasertib in the resistant E17K models. Sensitivity to mTOR inhibition was maintained in capivasertib resistant models, with mTOR inhibition re-sensitizing cells to capivasertib. In these models, acquired resistance to capivasertib occurs through upregulation of ER signalling and rewiring of pathway signalling to bypass AKT inhibition and reactivate mTORC1. Targeting these mechanisms could prolong the use of capivasertib, with future work focusing on validating these mechanisms and re-sensitizing drug combinations in other AKT1 mutant models & PDOs. Citation Format: Sarah Mearns, Alex Pearson, Li-Xuan Sim, Rosalind Cutts, Prithika Sritharan, Heena Shah, Aditi Gulati, Stuart Williamson, Simon Barry, Elza De-Bruin, Nicholas C. Turner. Mechanisms of acquired resistance to AKT inhibitor capivasertib in AKT1 mutant patient derived breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB450.

Regulatory role of miR-125a expression with respect to its target genes LIFR, ERBB2 and STAT3 in the pathogenesis of recurrent pregnancy losses.

Studies have investigated miR-125a for its predictable role in recurrent pregnancy loss (RPL) cases to regulate many biological events required for the maintenance of pregnancy by regulating its confirmed target genes LIFR, ERBB2 and STAT3. The present study included 40 cases of women with at least two RPLs in ≤20 weeks of gestation against 40 healthy multiparous women without a previous history of abortion. Expression analysis of ERBB2, LIFR, STAT3 and miR-125a was conducted by quantitative real-time PCR (qPCR). The expression of miR-125a was significantly lower in the plasma of RPL cases (P = 0.0001) and showed a significantly increased mean expression level in product of conception (2.56-fold, P < 0.0001). Among the target gene of miR-125a, ERBB2 and STAT3 gene expression level was significantly increased (2.58-fold, P = 0.04; 1.87-fold, P = 0.025), respectively in RPL cases while the LIFR gene revealed comparable expression (P = 0.64). Furthermore, expression analysis of ERBB2 gene with respect to its regulatory miR-125a cases depicted a significant association (P = 0.0005). Kaplan-Meier survival analysis revealed cases with low miR-125a expression had significantly shorter time to miscarriages, (log-rank P = 0.02). Also, decreased expression of miR-125a significantly conferred >2-fold increased risk for RPL (HR = 2.34: P < 0.05). The overall conclusion of the study was that altered miR-125a expression may cause deregulation in target genes LIFR, ERBB2 and STAT3 resulting in adverse consequence in the outcome of pregnancy.

Peri-hilar cholangiocarcinoma (phCCA): A comparative comprehensive genomic profiling study.

542 Background: CCA is a heterogenous group of malignancies that arise from epithelium of the biliary tree. The comparison of the genomic landscapes that can influence therapy selection of phCCA from other types of intra- and extra-hepatic CCA (ih/ehCCA) are not well-known. We queried differences in comprehensive genomic profiles (CGP) of CCAs and comparing genomic alterations (GA) in phCCA and other types of CCA. Methods: DNA extracted from 110 cases of phCCA, 743 cases of common bile duct CCA (cbdCCA) and 9178 cases of intrihCCA underwent hybrid capture-based CGP to evaluate GA, MSI status, TMB levels, genomic ancestry, genomic signature, HRD score and germline status. phCCA cases were confirmed at surgery and pathology as originating from either the left, right or common hepatic ducts. cbdCCA cases were confirmed either by CBD biopsies or Whipple procedures. PD-L1 expression was determined by IHC using the Dako 22C3 assay using the tumor proportional score (TPS) system. Results: Patient characteristics were similar (Table). The GA/tumor and frequencies of European ancestry were similar. Both phCCA and cbdCCA featured significantly greater frequency of ERBB2 GA than ihCCA (P=.002) and lower frequencies of FGFR2 GA (P=.001) and IDH1 GA (P=.006). ihCCA featured significantly higher frequencies of FGFR2 (11.7%) and IDH1 (13.9%; P=.006) GA than either phCCA or cbdCCA. cbdCCA had a significantly higher frequency of KRAS GA than phCCA (P=.015) and ihCCA (P&lt;.001). The KRAS G12C frequency reached 5.9% of KRAS mutated ihCCA. GA in BRAF, PIK3CA, CDKN2A and MTAP were not significantly different. TP53 GA were higher in cbdCCA than phCCA (P=0.011) and combined phCCA and cbdCCA (ehCCA) were higher than ihCCA (P=.071). MSI status, TMB levels and PD-L1 expression was similarly low in all 3 groups. Positive homologous recombination deficiency (HRD) scores based on %gLOH and high frequencies of MMR genomic signatures were similar in all 3 groups. Conclusions: phCCA appears to be a distinctive form of ehCCA featuring significantly higher frequencies of potentially targetable ERBB2 and lower frequencies of targetable FGFR2 and IDH1 mutations, when compared to ihCCA. Predictive IO markers were similarly low in both ihCCA and ehCCA.[Table: see text]

Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study

Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

Treatments During Pregnancy Targeting ERBB2 and Outcomes of Pregnant Individuals and Newborns

Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy. To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents. For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included. The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents. The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis. A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]). In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.

The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System

The activation of members of the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and have profound consequences both in physiological and pathological conditions. Within the nervous system, the neuregulin (NRG)/ErbB3 signaling plays a crucial role in promoting the formation and maturation of excitatory synapses. Noteworthy is ErbB3, which is actively involved in the process of cerebellar lamination and myelination. All members of the ErbB-family, in particular ErbB3, have been observed within the nuclei of various cell types, including both full-length receptors and alternative variants. One of these variants was detected in Schwann cells and in glioblastoma primary cells where it showed a neuregulin-dependent expression. It binds to promoters’ chromatin associated with genes, like ezrin, involved in the formation of Ranvier’s node. Its nucleolar localization suggests that it may play a role in ribosome biogenesis and in cell proliferation. The regulation of ErbB3 expression is a complex and dynamic process that can be influenced by different factors, including miRNAs. This mechanism appears to play a significant role in glioblastoma and is often associated with a poor prognosis. Altogether, the targeting of ErbB3 has emerged as an active area of research in glioblastoma treatment. These findings highlight the underappreciated role of ErbB3 as a significant receptor that can potentially play a pivotal role in diverse pathologies, implying the existence of a shared and intricate mechanism that warrants further investigation.

Peptides for Dual Targeting of ErbB1 and ErbB2: Blocking EGFR Cell Signaling Transduction Pathways for Cancer Chemotherapy.

Cancer is one of the most deadly diseases involving dysregulated cell proliferation. Chemotherapeutic drugs have serious drawbacks of nonspecific toxicity and drug resistance. Tyrosine kinases are a significant class of enzymes of protein kinases. The four members of the trans-membrane family of tyrosine kinase receptors known as the human epidermal growth factor receptors (EGFR), ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, are overexpressed in many forms of cancer. These receptors are crucial for cell division, invasion, metastasis, angiogenesis, and uncontrolled activation of cancer cells. In this context, an attractive combination of anticancer drug targets is ErbB1 and ErbB2. Numerous cancer types exhibit overexpression of ErbB1 and ErbB2, which is linked to poor prognosis and causes resistance to ErbB1-targeted therapy. Further, it has been reported in recent years that the use of peptides as anticancer agents have the potential to circumvent the drawbacks of the currently used chemotherapeutic drugs. Among them, short peptides have several advantages when compared to small molecules. The present report reviews the importance of tyrosine kinases as targets for cancer, the role of peptides as therapeutic agents, and the investigations that have been carried out by earlier workers for targeting both ErbB1 and ErbB2 using therapeutic peptides.

Enhanced detection and characterization of targetable EGFR and ERBB2 exon20 insertion mutations in urothelial carcinoma.

e16500 Background: EGFR and ERBB2 exon 20 insertion (exon20ins) driver mutations are well described in non-small cell lung cancer due to their resistance to early generation EGFR tyrosine kinase inhibitors. This has led to the development and ultimate approval of exon20ins specific inhibitors, such as mobocertinib. Previous studies have reported EGFR and ERBB2 exon20ins mutations in 0.15%-1.91% of urothelial carcinoma (UC) patients, but this is likely an underrepresentation as indel variants are often under detected by commonly used NGS-variant analysis tools. Additionally, little is known about the biological consequences of EGFR and ERBB2 exon20ins mutations in UC. In this study, we aimed to: 1) characterize the prevalence of EGFR and ERBB2 exon20ins mutations in UC; 2) assess how EGFR and ERBB2 exon20ins mutations impact malignant transformation; and 3) evaluate the sensitivity of UC cell lines with the exon20ins to mobocertinib. Methods: UC patient datasets were realigned using the indel caller, ABRA2, then EGFR and ERBB2 exon20ins frequencies were calculated. Next, parental KT1970 urothelial cells expressing either EGFR WT, ERBB2 WT, or exon20ins mutation constructs (EGFRinsH [insH] or ERBB2insYVMA [YVMA]) were generated and in vitro transformation assays were performed. Anchorage-independent growth was assessed with soft agar assay. Engineered urothelial organoids with various exon20ins variants were created to assess for their ability to differentiate. Finally, sensitivity to erlotinib and mobocertinib was determined. Results: ABRA2 identified a prevalence of ERBB2 and EGFR Exon20ins mutations in 2.5% (7/275) of urothelial tumors in the IMVigor210 patient cohort. ERBB2 insYVMA expressing organoids had the highest basal marker (KRT5) expression in proliferation media which decreased in differentiation media. In the soft agar assay, YVMA cells had a 9.26 fold increase in colony formation (CF) compared to the ERBB2 WT counterpart and insH had a 6.02 fold increase in CF over the EGFR WT counterpart. The IC50 for mobocertinib (M) was significantly lower than erlotinib (E) in the exon20ins cell lines (insH M: 0.123 uM, E:10.69 uM / YVMA M: 0.57 uM, E: 13.54 uM). The difference in IC50 values for mobocertinib vs erlotinib in the WT cells was less pronounced. Conclusions: The prevalence of EFGR and ERBB2 exon20 insertion mutations is likely unrepresented in urothelial carcinoma by current variant calling pipelines. The ERBB2 YVMA mutation showed a more aggressive phenotype and possible basal pattern in vitro which may have implications in terms of prognosis and treatment considerations. Both EGFR and ERBB2 exon20ins urothelial cells were more sensitive to mobocertinib. This study provides evidence that exon20ins specific inhibitors could offer additional targeted therapy options for patients with urothelial cancer who have EGFRinsH and ERBB2insYVMA mutations.

Lipid Metabolism Reprogramming and Trastuzumab Resistance in Breast Cancer Cell Lines Overexpressing the ERBB2 Membrane Receptor.

Trastuzumab (Tz), an antibody targeting ERBB2, has significantly improved the prognosis for breast cancer (BCa) patients with overexpression of the ERBB2 receptor. However, Tz resistance poses a challenge to patient outcomes. Numerous mechanisms have been suggested to contribute to Tz resistance, and this study aimed to uncover shared mechanisms in in vitro models of acquired BCa Tz resistance. Three widely used ERBB2+ BCa cell lines, adapted to grow in Tz, were examined. Despite investigating potential changes in phenotype, proliferation, and ERBB2 membrane expression in these Tz-resistant (Tz-R) cell lines compared to wild-type (wt) cells, no common alterations were discovered. Instead, high-resolution mass spectrometry analysis revealed a shared set of differentially expressed proteins (DEPs) in Tz-R versus wt cells. Bioinformatic analysis demonstrated that all three Tz-R cell models exhibited modulation of proteins associated with lipid metabolism, organophosphate biosynthesis, and macromolecule methylation. Ultrastructural examination corroborated the presence of altered lipid droplets in resistant cells. These findings strongly support the notion that intricate metabolic adaptations, including lipid metabolism, protein phosphorylation, and potentially chromatin remodeling, may contribute to Tz resistance. The detection of 10 common DEPs across all three Tz-resistant cell lines offers promising avenues for future therapeutic interventions, providing potential targets to overcome Tz resistance and potentially improve patient outcomes in ERBB2+ breast cancer.

Small Cell Lung Cancer in Light/Never Smokers - A Role for Molecular Testing?

This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor-sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have light/never smoking histories in order to help understand the incidence and ultimate optimal management strategies.

MicroRNA-592 Inhibits the Growth of Ovarian Cancer Cells by Targeting ERBB3.

Objectives: Ovarian cancer is the most lethal gynecologic malignancy, and targeted therapy for different pathological types and molecular phenotypes is urgent to be studied. Studies have shown that MicroRNA-592 (miR-592) plays an important negative regulatory role in the occurrence of gastrointestinal malignancies, breast cancer, non-small cell lung cancer, and glioma, but the expression of miR-592 in ovarian cancer and the mechanism of action are still unclear. Methods: The expressions of miR-592 were examined by RT-PCR and Western Blot. Cell viability and migratory capacity were detected by CCK-8 and transwell assay. TargetScan (http://www.targetscan.org) was analyzed to predict potential targets of miR-592. Then Dual-luciferase reporter gene assay was performed to verify the targeting relationship between miR-592 and ERBB3. A mouse xenograft model was applied to confirm the effect of miR-592. Results: In our study, we found that the expression of miR-592 is reduced in epithelial ovarian cancer tissues. The exogenous expression of miR-592 inhibits the proliferation, migration, and invasion in epithelial ovarian cancer tumor cells. Furthermore, the exogenous expression of miR-592 inhibits tumor growth in the nude mouse xenograft model. Therefore, miR-592 may play a role of tumor suppressor miRNA in the occurrence and development of ovarian cancer. Further experiments demonstrated that tumor-related ERBB3 is a target gene mediated by miRNA-592. The dual-luciferase reporter system was used to identify miRNA-592 target genes; qPCR and Western Blot were used to detect the expression of ERBB3. Mechanical experiments confirmed that miRNA-592 negatively regulated ERBB3.Conclusion: Together, these findings identify a heretofore unrecognized link between miR-592 and ERBB3 and suggest that targeting on miR-592 warrants attention as a novel and potential therapeutic strategy for ovarian cancer.

Molecular characterization of adenocarcinomas arising in the urinary bladder following augmentation cystoplasty: a multi-institutional study

Development of malignancy is a rare complication following augmentation cystoplasty, and the majority of tumors observed in this setting are adenocarcinomas. Here, we sought to genetically profile these tumors by targeted DNA sequencing of a multi-institutional cohort of adenocarcinomas that developed in the urinary bladder following augmentation cystoplasty. Carcinomas arising in the urinary bladder of patients with history of augmentation cystoplasty were obtained from 4 major academic institutions, with cases diagnosed as urothelial carcinoma excluded from the study. The cases were analyzed using a DNA sequencing panel that includes 529 genes and genome-wide copy number assessment. The most frequently altered genes included TP53, KRAS, and MYC, and the vast majority of cases demonstrated mutational profiles consistent with gastrointestinal adenocarcinomas. One case demonstrated an EML4::ALK fusion together with an MSH3 frameshift mutation and hypermutated phenotype, characteristic of a rare but aggressive subtype of colorectal adenocarcinoma that may benefit from targeted ALK inhibition therapy. Importantly, six other tumors in the cohort also had potentially targetable molecular alterations, involving ATM (2 cases), BRCA1 (2 cases), EGFR (1 case), and ERBB2 (1 case). To our knowledge, this study represents the most comprehensive molecular characterization to date of adenocarcinomas arising in the urinary bladder following augmentation cystoplasty. Despite the unique environment of the augmented tissue, the resulting tumors demonstrate a spectrum of driver mutations similar to that of primary gastrointestinal adenocarcinomas. Importantly, molecular alterations potentially amenable to targeted therapy were identified in the majority of cases.

Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene.

Simple SummaryColorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. Although ERBB2 (also known as HER-2) has an important therapeutic role in breast and esophagogastric cancer, there are no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the landscape of ERBB2-positive mCRC.Colorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. ERBB2 amplification (also known as HER-2) has been identified in 2–3% of patients with mCRC, but there are currently no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the molecular structure of ERBB2, clinical features of these patients, diagnosis of ERBB2 alterations, and the most relevant clinical trials with ERBB2-targeted therapies in mCRC.

ErbB3-Targeting Oncolytic Adenovirus Causes Potent Tumor Suppression by Induction of Apoptosis in Cancer Cells.

Cancer is a multifactorial and deadly disease. Despite major advancements in cancer therapy in the last two decades, cancer incidence is on the rise and disease prognosis still remains poor. Furthermore, molecular mechanisms of cancer invasiveness, metastasis, and drug resistance remain largely elusive. Targeted cancer therapy involving the silencing of specific cancer-enriched proteins by small interfering RNA (siRNA) offers a powerful tool. However, its application in clinic is limited by the short half-life of siRNA and warrants the development of efficient and stable siRNA delivery systems. Oncolytic adenovirus-mediated therapy offers an attractive alternative to the chemical drugs that often suffer from innate and acquired drug resistance. In continuation to our reports on the development of oncolytic adenovirus-mediated delivery of shRNA, we report here the replication-incompetent (dAd/shErbB3) and replication-competent (oAd/shErbB3) oncolytic adenovirus systems that caused efficient and persistent targeting of ErbB3. We demonstrate that the E1A coded by oAd/shErbB, in contrast to dAd/shErbB, caused downregulation of ErbB2 and ErbB3, yielding stronger downregulation of the ErbB3-oncogenic signaling axis in in vitro models of lung and breast cancer. These results were validated by in vivo antitumor efficacy of dAd/shErbB3 and oAd/shErbB3.

Comprehensive genomic profiling of MET rare tumors in China.

e15058 Background: The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, commonly activated by amplification, mutation and fusion. Methods: Rare tumor was defined as solid tumors with an incidence lower than 2.5/100,000 per year. We retrospectively analyzed the next-generation sequencing and clinicopathological data of 3453 Chinese rare tumors patients in the Geneplus database, including 1021 genes, MSI loci, tumor mutational burden (TMB), and programmed cell death ligand-1 (PD-L1) expression analysis information. Results: MET-positive was identified in 115 patients (3.3%), including 109 cases of amplification (3.2%), 8 cases of exon 14 skipping (0.2%) and 1 cases of fusion. The prevalence of MET-positive varied widely across tumors systems and subtypes. Urinary, neural, skin and respiratory systems were the top 4 systems with 8.3% (1/12), 7.9% (58/732), 4.2% (1/24) and 2.9% (6/207) MET-positive rate, respectively. Considering the tumor subtypes, glioblastoma, sarcomatoid carcinoma, neuroendocrine tumor and glioma were higher, reaching 15.7% (16/102), 13.2% (7/53), 9.8% (4/41), and 7.4% (36/487) respectively (Table). Totally, 73.0% of patients had at least one common targetable gene mutation, including ATM，BRAF，BRCA，CDKN2A，EGFR substitution, ERBB2, FGFR1,2,3, KIT, NF1, PIK3CA, PTEN and RET. The proportions of TMB-H (≥9 mut/Mb) and MSI-H were very low, with only 8.9% and 2.2%, while PD-L1 positive rate reached to 60.9%. Conclusions: The treatment options for rare tumors are still limited. The approval of MET receptor tyrosine kinase has brought hope to patients with Non-Small Cell Lung Cancer. The MET-positive rate in rare tumors is higher than 2.7% in lung adenocarcinoma, so MET receptor tyrosine kinase have great application potential in rare tumors. However, since most patients co-occurred with other targetable driver mutations or PD-L1 positive, how to choose the best treatment strategy should be solved. The deployment of the best treatment strategy is a problem that should be solved in the follow-up study.[Table: see text]

Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidium monnieri in Treating Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with a high mortality rate globally. For thousands of years, Cnidium monnieri has been used to treat human ailments and is regarded as a veritable treasure trove for drug discovery. This study has investigated the key active phytochemicals and molecular mechanisms of Cnidium monnieri implicated in curing HCC. We utilized the TCMSP database to collect data on the phytochemicals of Cnidium monnieri. The SwissTargetPrediction website tool was used to predict the targets of phytochemicals of Cnidium monnieri. HCC-related genes were retrieved from OncoDB.HCC and Liverome, two liver-cancer-related databases. Using the DAVID bioinformatic website tool, Gene Ontology (GO) and KEGG enrichment analysis were performed on the intersecting targets of HCC-related genes and active phytochemicals in Cnidium monnieri. A network of active phytochemicals and anti-HCC targets was constructed and analyzed using Cytoscape software. Molecular docking of key active phytochemicals was performed with anti-HCC targets using AutoDock Vina (version 1.2.0.). We identified 19 active phytochemicals in Cnidium monnieri, 532 potential targets of these phytochemicals, and 566 HCC-related genes. Results of GO enrichment indicated that Cnidium monnieri might be implicated in affecting gene targets involved in multiple biological processes, such as protein phosphorylation, negative regulation of the apoptotic process, which could be attributed to its anti-HCC effects. KEGG pathway analyses indicated that the PI3K–AKT signaling pathway, pathways in cancer, proteoglycans in cancer, the TNF signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance are the main pathways implicated in the anti-HCC effects of Cnidium monnieri. Molecular docking analyses showed that key active phytochemicals of Cnidium monnieri, such as ar-curcumene, diosmetin, and (E)-2,3-bis(2-keto-7-methoxy-chromen-8-yl)acrolein, can bind to core therapeutic targets EGFR, CASP3, ESR1, MAPK3, CCND1, and ERBB2. The results of the present study offer clues for further investigation of the anti-HCC phytochemicals and mechanisms of Cnidium monnieri and provide a basis for developing modern anti-HCC drugs based on phytochemicals in Cnidium monnieri.

Targeting ErbB3 and Cellular NADPH/NADP+ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers.

Melanoma is a serious health challenge. Ferroptosis is a regulated form of oxidative cell death that shows varied efficacy in melanoma. We aimed to better understand the molecular basis for this differential ferroptosis sensitivity. We find that elevated expression of ErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homologue 3) associates with ferroptosis resistance and that ErbB3 knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG (reduced/oxidized glutathione) and that of NADPH/NADP+ (reduced/oxidized nicotinamide adenine dinucleotide phosphate), together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several small molecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP+ and GSH/GSSG ratios, concomitantly sensitizing the melanomas to ferroptosis activators. These findings point to a previously unrecognized role of ErbB3 in ferroptosis sensitivity and provide new insight into pathways that regulate this cell death process.

Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/d mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.