ERBB3 overexpression

Consistent with the initial results, HER3-ECD-targeting PAbs were cytotoxic in several human epithelial tumor cell lines and exerted antitumor effects in vivo. These results support the value of HER3 as a tumor antigen and the effector mechanisms of HER3-specific therapeutic MAbs, while suggesting the potential of the proposed vaccine candidate for the treatment of HER3-expressing carcinomas.

P1/2, N=81, Recruiting, Cancer Research UK | N=135 --> 81

Treatment of mice with BxPC3 human pancreatic cancer xenografts showed that a combination of ZHER3-ABD-ZHER3-mcDM1 and its cytostatic analog ZHER3-ABD-ZHER3 was efficacious and superior to treatment with only ZHER3-ABD-ZHER3, providing tumor growth inhibition and longer median survival (90 d) in comparison to monotherapy (68 d) and vehicle control (49 d). ZHER3-ABD-ZHER3-mcDM1 was found to be a potent drug conjugate for the treatment of HER3-expressing tumors in mice.

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.

These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.

Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.

In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling and serum PSA despite low intraprostatic androgen, suggesting ERBB3 OE as a prospective biomarker for ligand-independent AR activation. In this context, ERBB3 OE could stratify patients for intensification of therapy in castration-sensitive disease and emphasizes the importance of biomarker-directed clinical trials with diverse populations.

In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2.

In vitro assays in HER2 /HER3 SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

The EGFR, HER2, and HER3 are overexpressed in lung cancer patient tumors, and monoclonal antibodies (mAbs), such as Herceptin against HER2, are used to treat breast cancer patients. Patients with EGFR mutations are treated with tyrosine kinase inhibitors, such as gefitinib or osimertinib...While the transactivation process is complicated, it is fast and occurs within minutes after adding NTS to cancer cells. This review emphasizes the use of tyrosine kinase inhibitors and SR48692 to impair transactivation and cancer growth.

HMBD-001 will next be evaluated in Part B in biomarker selected mCRPC with Enzalutamide. Trials of HMBD-001 in squamous NSCLC and NRG1 fusions are also planned for Q3/4 2023.

Table: 688P Pharmacokinetics of HMBD-001 on day 1 of dosing Conclusions The pharmacokinetic data generated to date are consistent with dose-dependent increases in drug exposure for HMBD-001. A T1/2 of approximately 12 days is predicted.

In the pre-ICB cohort, an association was found between high HER3 expression (≥2+) and overall survival after anti-PD-1-based immunotherapy. Overall, our results indicate that HER3 is a promising therapeutic avenue in cutaneous melanoma worthy of further clinical evaluation.

Our work demonstrates that β-catenin is highly expressed in BC and it synergically promotes formation and progress of BC with HER2. β-catenin binds with HER2 leading to enhanced interaction with SRC and resistance to trastuzumab.

When the tumor of the cohort reached an average volume of 250mm3, mice were treated or not with cetuximab...HER3 targeting (by means of the novel antibody drug conjugate patritumab deruxtecan) and AREG/EREG silencing strongly affected cell viability, suggesting that sensitive models rely on these pathways for their growth.ConclusionWe identified a subset of GEA sensitive to EGFR targeting drugs and propose HER3 and AREG/EREG expression as markers for patients' selection. Further validation on GEA samples derived from clinical trials evaluating effectiveness of EGFR targeting is needed. We believe that, despite the negative results of clinical trials so far, EGFR can represent a suitable target in molecularly selected GEA patients.

HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3 CD57 NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.

Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. Clinical trial information: NCT04348747.

HER3 is highly abundant in BM of BCa and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM specific trials that target HER3 are warranted.

In vivo drug efficacies are being screened using cell-derived hepatocellular carcinoma (HCC) and gastric carcinoma xenografts, as well as patient-derived gastric and pancreatic xenograft models. Collectively, these results suggest that BCG022 has the potential to be a novel therapeutic option for HER3 and MET co-expressing tumors.

Patritumab-Deruxtecan (U3-1402), a HER3-targeting ADC, showed clinical response in a subset of EGFR mutant and TKI resistant lung cancers in a Phase 1 study, albeit with toxicities including severe interstitial lung disease (ILD) and high grade cytopenias. In conclusion, HMBD-501 represents a next generation HER3 targeting ADC that has a potentially best-in-class efficacy and tolerability profile. Our findings strongly support the development of HMBD-501 as a promising candidate in the treatment of HER3 expressing solid tumors.

EGFR and MET overexpressed in tumor tissue of TNBC specimens while smaller proportion of HER3+ cells were limited to tumor as compared to stroma. HER3 appears to be altered by neoadjuvant chemotherapy. EGFR and MET expression correlated with CD45+ immune cells.

Background: HER3, a member of the ERBB family of receptor tyrosine kinases that activates multiple oncogenic signaling pathways, is overexpressed in 50-70% of breast cancers (BC). The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC.

In conclusion, the present study identified 14 EMT-related genes and 30 genes involved in the PI3K/AKT/mTOR pathway in cervical cancer, and they might provide novel clues for future treatment. The MMP family may be a notable factor associated with tumor cells and immune cells.

An experimental therapy study using Ec1-LoPE and MM-121 in mice bearing EpCAM- and HER3-expressing BxPC3 xenografts demonstrated the feasibility of the therapy. Further development of the co-targeting approach using HER3 and EpCAM could therefore be justified.

The latter is more pronounced in the drug withdrawal phase, where the de-inhibition of Her2 creates an acute surge in the downstream signaling pathways and exacerbates the proteostatic imbalance. Therefore, the acquired resistance mechanisms to oncogenic kinase inhibitors may create secondary vulnerabilities that could be exploited in the clinic.

P1/2, N=19, Terminated, Taiho Oncology, Inc. | Active, not recruiting --> Terminated; The study was stopped due to unacceptable toxicity during the dose-escalation portion (Phase 1) of the study and did not progress to Phase 2

PD-L1 expression was demonstrated in 3 out of 13 HER-3‑positive patients and 2 out of 2 HER-3‑positive TNBC patients. There was a strong correlation between positive HER-3 and PD-L1 TNBC expression (p = Keywords: breast cancer, HER family, overexpression, HER-3, HER-2, PD-L1, TNBC.

The primary objective of cohort 4 is to evaluate the PK of this formulation during the first treatment cycle. Secondary objectives include the evaluation of PK, safety, tolerability, immunogenicity, and efficacy.

TP53-mutant, basal-like PDX models were more likely to show long-term responses to HER3-DXd than luminal B PDX models. Compared to irinotecan, HER3-DXd induced improved antitumor activity inducing higher and persistent levels of S-phase DNA damage.

The results from the study show that Z-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.

Furthermore, HERC3 could regulate the ubiquitination of p21 and further modulate protein expression of c-Myc and p21 via regulating RPL23A. HERC3 controlled CRC proliferation, the cell cycle and regulated the c-Myc/p21 axis via directly targeting RPL23A for ubiquitination degradation.

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.

This study showed upregulation and hypomethylation of the HER3 gene in CRC cases. Epigenetic alterations were also found in the adjacent normal colon tissues. Thus, upregulation and hypomethylation of HER3 may play a key role in carcinogenesis of CRC. Hypomethylation of CpG islands might be associated with early steps during carcinogenesis. The findings of this biomarker serve a powerful approach to improve the current diagnostic and therapeutic measures.

Cell line UM-SCC-11B revealed a strong resistance to lapatinib under 3D cell culture conditions, while a good response to TKI therapy was observed under 2D cell culture conditions...The results of the present study represent an idea of how signalling mechanisms of cancer cells can be changed using different cell culture methods. Overall, 3D cell culture could be an important component in the analysis of resistance mechanisms in cancer therapy.

Panobinostat and romidepsin induced growth inhibition and apoptosis in HER3high-TNBC cells via downregulating HER3 expression and inhibiting PI-3K/Akt signaling. Significantly, HDACis in combination with an EGFR inhibitor (gefitinib) or an Akt inhibitor (Akti1/2) synergistically enhanced the anti-survival effects on HER3high-TNBC cells... HDAC inhibitors exhibits potent inhibitory effects on HER3high-TNBC cells via downregulation of FOXA1-mediated repression of HER3 gene transcription. Our data suggest that epigenetic targeting of FOXA1-HER3/EGFR-PI-3K/Akt signaling axis may be an effective therapeutic strategy for eradication of HER3high-TNBC tumors.

The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC. We are currently validating the synergy in endocrine-resistant ER+ BC xenograft models.