HER3: Updates and current biology function, targeted therapy and pathologic detecting methods.

Being a member of the EGFR tyrosine kinase family, HER3 has been shown to be overexpressed in a number of cancers, including breast cancer (BC). The kinase activity of HER3 is extremely low, and it forms heterodimers with partners, HER2 in particular, that promote biological processes like cell migration, survival, and proliferation by activating downstream carcinogenic signaling pathways. The overexpression of HER3 is also directly linked to tumor invasion, metastasis, and a poor prognosis. Despite the relatively low expression of HER3 compared to EGFR and HER2, a lot of targeted drugs are making their way into clinical trials and seem to have a bright further. This review aims to summarize the relationship between HER3 overexpression, mutations, and carcinogenicity and drug resistance, starting from the unique structure and kinase activity of HER3. Simultaneously, numerous approaches to HER3 targeted therapy are enumerated, and the clinical detection methods for HER3 that are commonly employed in pathology are sorted and contrasted to offer physicians a range of options. We think that a better knowledge of the mechanisms underlying HER3 in tumors and the advancement of targeted HER3 therapy will contribute to an improved prognosis for cancer patients and an increase in the efficacy of anticancer therapies.

Neuregulin 1 Signaling Attenuates Tumor Necrosis Factor α-Induced Female Rat Luteal Cell Death.

The corpus luteum (CL) is a transient ovarian endocrine structure that maintains pregnancy in primates during the first trimester and in rodents during the entire pregnancy by producing steroid hormone progesterone (P4). CL lifespan, growth, and differentiation are tightly regulated by survival and cell death signals through luteotrophic and luteolytic factors, including the epidermal growth factor (EGF)-like factor family. Neuregulin 1 (NRG1), a member of the EGF family, mediates its effect through ErbB2/3 receptors. However, the functional role of NRG1 in luteal cells (LCs) is unknown. Thus, this study investigated the role of NRG1 and its molecular mechanism of action in rat LC. Our experimental results suggest a strong positive correlation between steroidogenic acute regulatory protein (StAR) and NRG1 expression in mid-CL and serum P4 and estrogen (E2) production. In contrast, there was a decrease in StAR and NRG1 expression and P4 and E2 production with an increase in tumor necrosis factor α (TNFα) expression in regressing CL. Further in vitro studies in LCs showed that the knockdown of endogenous Nrg1 promoted the expression of proinflammatory and proapoptotic factors and decreased prosurvival factor expression. Subsequently, treatment with exogenous TNFα under these experimental conditions profoundly elevated proinflammatory and proapoptotic factors. Further analysis demonstrated that the phosphorylation status of ErbB2/3, PI3K, Ak strain transforming or protein kinase B (Akt), and ErK1/2 was significantly inhibited under these experimental conditions, whereas the treatment of TNFα further inhibited the phosphorylation of ErbB2/3, PI3K, Akt, and ErK1/2. Collectively, these studies provide new insights into the NRG1-mediated immunomodulatory and prosurvival role in LCs, which may maintain the function of CL.

ESM1 facilitates the EGFR/HER3-triggered epithelial-to-mesenchymal transition and progression of gastric cancer via modulating interplay between Akt and angiopoietin-2 signaling.

Gastric cancer (GC) poses global challenges due to its difficult early diagnosis and drug resistance, necessitating the identification of early detection markers and understanding of oncogenic pathways for effective GC therapy. Endothelial cell-specific molecule 1 (ESM1), a secreted glycoprotein, is elevated in various cancers, but its role in GC remains controversial. In our study, ESM1 was elevated in GC tissues, and its concentration was correlated with progression and poorer patient prognosis in independent cohorts. Functionally, ESM1 expression promoted proliferation, anoikis resistance, and motility of GC cells, as well as tumor growth in PDOs and in GC xenograft models. Mechanistically, ESM1 expression triggered the epithelial-to-mesenchymal transition (EMT) of GC cells by enhancing epidermal growth factor receptor (EGFR)/human EGFR 3 (HER3) association and activating the EGFR/HER3-Akt pathway. Additionally, angiopoietin-2 (ANGPT2) was found to be highly correlated with ESM1 and interplayed with Akt to induce the EMT and cancer progression. Use of a signal peptide deletion mutant (ESM1-19del) showed that the secreted form of ESM1 is crucial for its protumorigenic effects by activating the EGFR/HER3-Akt/ANGPT2 pathway to promote the EMT. Patients with high levels of both ESM1 and ANGPT2 had the poorest prognoses. Furthermore, therapeutic peptides successfully inhibited ESM1's induction of the aforementioned signals and motility of GC cells. ESM1's oncogenic role in GC involves activating the EGFR/HER3-Akt/ANGPT2 pathway, presenting a potential therapeutic target for GC.

Investigating the Co-Expression Rate of HER2 and HER3 Biomarkers in Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Many types of cancer express the HER2/HER3 heterodimer, which is a crucial oncogenic unit. Research has shown that when these two biomarkers are expressed together, it correlates with higher tumor aggressiveness and lower overall survival rate. Therefore, many therapies have been developed to target both biomarkers simultaneously. This study aims to collect data on the co-expression levels of these biomarkers across different types of cancers. METHODS: A comprehensive search was conducted across PubMed, Scopus, Embase, and Web of Science databases to identify relevant studies. The event rates and their corresponding 95% confidence intervals were calculated. Heterogeneity, subgroup, and meta-regression analyses were conducted based on patients' residency region, age, and gender. The protocol of this study was registered in PROSPERO under ID: CRD42024504256. RESULTS: We have detected 60 studies that met all of the inclusion criteria for our research. Out of these, we have focused on a total of 19 studies (with 6,079 participants) related to breast cancer, 9 studies (with 829 participants) related to lung cancer, 6 studies (with 1423 participants) related to gastric cancer, and 4 studies (with 802 participants) related to colorectal cancer for conducting our meta-analysis. According to our results, the co-expression rate of HER2 and HER3 in breast cancer patients is 18.5% (95%CI 11.7-27.9), in colorectal cancer patients is 17.1% (95%CI 2.4-63.4), in gastric cancer patients is 11.3% (95%CI 4.2-17.2), and in lung cancer patients is 12.7% (95%CI 5.2-22.8). The co-expression of HER2 and HER3 in lung cancer has a significant association with patients' gender (P=0.038). CONCLUSION: The study found that HER2 and HER3 biomarkers, which are targets for different therapies, are co-expressed in various types of cancer.

SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer.

BACKGROUND: In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer. METHODS: SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding. RESULTS: SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo. CONCLUSION: We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

ERBB3 targeting: A promising approach to overcoming cancer therapeutic resistance.

Human epidermal growth factor receptor-3 (ERBB3) is a member of the ERBB receptor tyrosine kinases (RTKs) and is expressed in many malignancies. Along with other ERBB receptors, ERBB3 is associated with regulating normal cell proliferation, apoptosis, differentiation, and survival, and has received increased research attention for its involvement in cancer therapies. ERBB3 expression or co-expression levels have been investigated as predictive factors for cancer prognosis and drug sensitivity. Additionally, the association between the elevated expression of ERBB3 and treatment failure in cancer therapy further established ERBB3-targeting therapy as a crucial therapeutic approach. This review delves into the molecular mechanisms of ERBB3-driven resistance to targeted therapeutics against ERBB2 and EGFR and other signal transduction inhibitors, endocrine therapy, chemotherapy, and radiotherapy. Using preclinical and clinical evidence, we synthesise and explicate how various aspects of aberrant ERBB3 activities-such as compensatory activation, signal crosstalk interactions, dysregulation in the endocytic pathway, mutations, ligand-independent activation, intrinsic kinase activity, and homodimerisation-can lead to resistance development and/or treatment failures. Several ERBB3-directed monoclonal antibodies, bispecific antibodies, and the emerging antibody-drug conjugate demonstrate encouraging clinical outcomes for improving therapeutic efficacy and overcoming resistance, especially when combined with other anti-cancer approaches. More research efforts are needed to identify appropriate biomarkers tailored for ERBB3-targeted therapies.

EV20/Omomyc: A novel dual MYC/HER3 targeting immunoconjugate.

MYC is one of the most important therapeutic targets in human cancer. Many attempts have been made to develop small molecules that could be used to curb its activity in patients, but most failed to identify a suitable direct inhibitor. After years of preclinical characterization, a tissue-penetrating peptide MYC inhibitor, called Omomyc, has been recently successfully used in a Phase I dose escalation study in late-stage, all-comers solid tumour patients. The study showed drug safety and positive signs of clinical activity, prompting the beginning of a new Phase Ib combination study currently ongoing in metastatic pancreatic adenocarcinoma patients. In this manuscript, we have explored the possibility to improve Omomyc targeting to specific cancer subtypes by linking it to a therapeutic antibody. The new immunoconjugate, called EV20/Omomyc, was developed by linking a humanised anti-HER3 antibody, named EV20, to Omomyc using a bifunctional linker. EV20/Omomyc shows antigen-dependent penetrating activity and therapeutic efficacy in a metastatic model of neuroblastoma. This study suggests that directing Omomyc into specific cell types using antibodies recognising tumour antigens could improve its therapeutic activity in specific indications, like in the paediatric setting.

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

A prospective study of HER3 expression pre and post neoadjuvant therapy of different breast cancer subtypes: implications for HER3 imaging therapy guidance.

PURPOSE: HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor. EXPERIMENTAL DESIGN: The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630). RESULTS: Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy. CONCLUSION: This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.

HER3 receptor and its role in the therapeutic management of metastatic breast cancer.

Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody-drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer.

Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

ErbB3 is required for hyperaminoacidemia-induced pancreatic α cell hyperplasia.

Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.

Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression.

Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.

Mechanisms of acquired resistance to HER2-Positive breast cancer therapies induced by HER3: A comprehensive review.

Receptor tyrosine kinases (RTKs) are cell surface receptors with kinase activity that play a crucial role in diverse cellular processes. Among the RTK family members, Human epidermal growth factor receptor 2 (HER2) and HER3 are particularly relevant to breast cancer. The review delves into the complexities of receptor tyrosine kinase interactions, resistance mechanisms, and the potential of anti-HER3 drugs, offering valuable insights into the clinical implications and future directions in this field of study. It assesses the potential of anti-HER3 drugs, such as pertuzumab, in overcoming resistance observed in HER2-positive breast cancer therapies. The review also explores the resistance mechanisms associated with various drugs, including trastuzumab, lapatinib, and PI3K inhibitors, providing insights into the intricate molecular processes underlying resistance development. The review concludes by emphasizing the necessity for further clinical trials to assess the efficacy of HER3 inhibitors and the potential of developing safe and effective anti-HER3 treatments to improve treatment outcomes for patients with HER2-positive breast cancer.

Long road towards effective HER3 targeting in breast cancer.

Breast cancer is a heterogeneous disease, encompassing multiple different subtypes. Thanks to the increasing knowledge of the diverse biological features of each subtype, most patients receive personalized treatment based on known biomarkers. However, the role of some biomarkers in breast cancer evolution is still unknown, and their potential use as a therapeutic target is still underexplored. HER3 is a member of the human epidermal growth factors receptor family, overexpressed in 50%-70% of breast cancers. HER3 plays a key role in cancer progression, metastasis development, and drug resistance across all the breast cancer subtypes. Owing to its critical role in cancer progression, many HER3-targeting therapies have been developed over the past decade with conflicting findings. Next-generation antibody-drug conjugates have recently shown promising results in solid tumors expressing HER3, including breast cancer. In this review, we discuss the HER3 role in the pathogenesis of breast cancer and its relevance across all subtypes. We also explore the new anti-HER3 treatment strategies, calling into question the significance of HER3 detection as crucial information in breast cancer treatment.

Trans-activating mutations of the pseudokinase ERBB3.

Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.

Pertuzumab Plus Trastuzumab in Patients With Biliary Tract Cancer With ERBB2/3 Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with biliary tract cancer (BTC) with ERBB2/3 amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab are reported. METHODS: Eligible patients had advanced BTC, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and a lack of standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16+ weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-nine patients were enrolled from February 2017 to January 2022, and all had advanced BTC with an ERBB2/3 alteration. One patient was not evaluable for efficacy. One complete response, eight partial responses, and two SD16+ were observed for DC and OR rates of 40% (90% CI, 27 to 100) and 32% (95% CI, 16 to 52), respectively. The null hypothesis of 15% DC rate was rejected (P = .0015). Four patients had at least one grade 3 adverse event (AE) or serious AE at least possibly related to treatment: anemia, diarrhea, infusion-related reaction, and fatigue. CONCLUSION: Pertuzumab plus trastuzumab met prespecified criteria to declare a signal of activity in patients with BTC and ERBB2/3 amplification, overexpression, or mutation.

HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer.

HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M. Patients whose tumor expressed the HER3 V104L variant had a reduced probability of overall survival compared to patients lacking a HER3 mutation whereas we did not find a statistically significant difference in overall survival of various cancer patients with the HER3 V104M mutation. Our data showed that HER2 inhibitors suppressed cell growth of HCC1569HER3KO cells stably expressing the HER3-V104L mutation. Cancer cell lines (SNU407, UC15 and DV90) with endogenous HER3-V104M mutation showed reduced cell proliferation and p-HER2/p-ERK1/2 expression with HER2 inhibitor treatment. Knock down of HER3 abrogated cell proliferation in the above cell lines which were overall more sensitive to the ERK inhibitor SCH779284 versus PI3K inhibitors. HER3-V104L mutation stabilized HER3 protein expression in COS7 and SNUC5 cells. COS7 cells transiently transfected with the HER3-V104L mutation in the presence of HER binding partners showed higher expression of p-HER3, p-ERK1/2 versus HER3-WT in a NRG-independent manner without any change in AKT signaling. Overall, this study shows the clinical relevance of the HER3 V104L and the V104M mutations and its response to HER2, PI3K and ERK inhibitors.

HER3 (ERBB3) amplification in liposarcoma - a putative new therapeutic target?

BACKGROUND: Liposarcomas are among the most common mesenchymal malignancies. However, the therapeutic options are still very limited and so far, targeted therapies had not yet been established. Immunotherapy, which has been a breakthrough in other oncological entities, seems to have no efficacy in liposarcoma. Complicating matters further, classification remains difficult due to the diversity of morphologies and nonspecific or absent markers in immunohistochemistry, leaving molecular pathology using FISH or sequencing as best options. Many liposarcomas harbor MDM2 gene amplifications. In close relation to the gene locus of MDM2, HER3 (ERBB3) gene is present and co-amplification could occur. Since the group of HER/EGFR receptor tyrosine kinases and its inhibitors/antibodies play a role in a broad spectrum of oncological diseases and treatments, and some HER3 inhibitors/antibodies are already under clinical investigation, we hypothesized that in case of HER3 co-amplifications a tumor might bear a further potential therapeutic target. METHODS: We performed FISH analysis (MDM2, DDIT3, HER3) in 56 archived cases and subsequently performed reclassification to confirm the diagnosis of liposarcoma. RESULTS: Next to 16 out of 56 cases needed to be re-classified, in 20 out of 54 cases, a cluster-amplification of HER3 could be detected, significantly correlating with MDM2 amplification. Our study shows that the entity of liposarcomas show specific molecular characteristics leading to reclassify archived cases by modern, established methodologies. Additionally, in 57.1% of these cases, HER3 was cluster-amplified profusely, presenting a putative therapeutic target for targeted therapy. CONCLUSION: Our study serves as the initial basis for further investigation of the HER3 gene as a putative therapeutic target in liposarcoma.