Targeting HER3 for cancer treatment: a new horizon for an old target

Uliano, Jacopo; Corvaja, C.; Curigliano, Giuseppe; Tarantino, Paolo

doi:10.1016/j.esmoop.2023.100790

Cited by 35 publications

(16 citation statements)

References 48 publications

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“…Our results further suggest that future investigations of HER2-targeting ADCs, including T-DXd, in HER2-low PDAC patients will have a large pool of potential patients eligible for enrollment. The HER3 abundance and activation state demonstrated here may also provide another avenue for exploration, though HER3 has not been established as a predictive biomarker [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors

Randall,

Hunt,

Nutcharoen

et al. 2024

Clin Proteom

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Metastatic pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 11%, necessitating identification of novel treatment paradigms. Tumor tissue specimens from patients with PDAC, breast cancer, and other solid tumor malignancies were collected and tumor cells were enriched using laser microdissection (LMD). Reverse phase protein array (RPPA) analysis was performed on enriched tumor cell lysates to quantify a 32-protein/phosphoprotein biomarker panel comprising known anticancer drug targets and/or cancer-related total and phosphorylated proteins, including HER2Total, HER2Y1248, and HER3Y1289. RPPA analysis revealed significant levels of HER2Total in PDAC patients at abundances comparable to HER2-positive (IHC 3+) and HER2-low (IHC 1+ /2+ , FISH−) breast cancer tissues, for which HER2 screening is routinely performed. These data support a critical unmet need for routine clinical evaluation of HER2 expression in PDAC patients and examination of the utility of HER2-directed antibody–drug conjugates in these patients.

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Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors

Randall,

Hunt,

Nutcharoen

et al. 2024

Clin Proteom

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“…While several studies demonstrated the effectiveness of combining crizotinib or lorlatinib with an EGFR inhibitor in inhibiting the growth of ALK inhibitor-resistant clones, the specific involvement of HER3 overexpression in this context has yet to be studied ( 10 , 34 ). Recent studies have reported therapeutic inhibition of the HRG1-HER3 interaction using HER3-directed antibodies, particularly bispecific antibodies targeting HER2/HER3 or HER3-directed antibody-drug conjugates in NRG1 ( HRG1 ) fusion-positive solid tumors ( 35 , 36 ). While there is a need to explore the physiological roles of HRG1 expression in ALK-TKI resistant lung cancers further, the combination of a HER3-targeting antibody with ALK-TKI may be an efficient treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

HER3 overexpression: a predictive marker for poor prognosis in advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors

Kim,

Ju,

Song

et al. 2024

Transl Lung Cancer Res

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Background Anaplastic lymphoma kinase (ALK)-targeted tyrosine kinase inhibitors (TKIs) improve patient survival; however, some patients develop ALK-TKI resistance with unidentified mechanisms. We investigated ErbB family and c-MET expression in patients with ALK-positive non-small cell lung cancer (NSCLC) to understand their roles in the ALK-TKI response. Methods We studied 72 patients with advanced ALK-positive NSCLC with EML4-ALK fusion variant subtyping and immunostaining for c-MET, EGFR, HER2, and HER3 on tissue specimens both pre- (primary) and post-treatment (secondary) with ALK-TKI. We investigated the association of their expression with survival outcomes and assessed the effectiveness of combining ALK and EGFR inhibitors in ALK-positive NSCLC cell lines stimulated with the HER3-specific ligand HRG1. Results High expression of c-MET, EGFR, HER2, and HER3 was observed in 4.9%, 18.0%, 1.6%, and 25.8% of primary tumors, respectively, and 18.5%, 37.0%, 10.7%, and 35.7% of secondary tumors, respectively. HER3 overexpression in primary tumors showed inferior survival (P=0.132). In the subgroup with EML4-ALK variant 1/2 (V1/V2), HER3 overexpression was significantly associated with inferior survival in both primary and secondary tumors (P=0.022 and P=0.004, respectively). Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. Conclusions 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.

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“…Its clinical journey began in 2016 with the initiation of the rst study, focusing on patients with HER3-positive metastatic breast cancer. Subsequently, it was extended to trials involving non-small cell lung cancer (NSCLC) and has reached the phase 3 stage [41]. An upcoming phase 2 trial (NCT05865990) is set to concentrate on patients with metastatic breast cancer or advanced NSCLC with active brain metastases, aiming to further assess its e cacy and safety.…”

Section: Sacituzumab Govitecan (Sg): Pioneering Trop2-targeted Therapymentioning

confidence: 99%

Antibody-Drug Conjugates for Breast Cancer: A Bibliometric Study and Clinical Trial Analysis

Xing,

Li,

Cui

et al. 2024

Preprint

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Background Breast cancer (BC) remains the most commonly diagnosed malignancy among women globally. Although early-stage BC typically presents with curative possibilities, advanced-stage disease, especially when complicated by metastatic involvement, is significantly limited in terms of efficacious therapeutic interventions, thereby establishing it as the second leading cause of cancer-related mortality in women. Antibody-Drug Conjugates (ADCs) epitomize a groundbreaking class of anti-neoplastic agents characterized by elevated specificity and targeting precision. Originating in theoretical frameworks of the 1960s, ADCs achieved Food and Drug Administration (FDA) approval in the year 2000 subsequent to exhaustive empirical scrutiny. These agents have been pivotal in reshaping the therapeutic approach to breast cancer, especially those subtypes with overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2). Comprising monoclonal antibodies, cytotoxic payloads, and conjugative linkers, ADCs function by specifically targeting antigens on cancer cells, thereby facilitating the intracellular delivery of the toxic payload. Current ADC modalities in BC treatment include ado-trastuzumab emtansine (T-DM1), fam-trastuzumab deruxtecan-nxki (T-DXd), and sacituzumab govitecan-hziy, among others. The present investigation endeavors to synthesize existing primary research outcomes through rigorous bibliometric and data analytical approaches, thereby elucidating the current epistemological landscape, delineating research foci, and identifying potential avenues for future innovation. Methods For bibliometric analysis, a comprehensive data set comprising 2,181 entries pertinent to ADCs in breast cancer was retrieved from the Web of Science Core Collection (WoSCC) spanning the years 1999 to 2023. This data was further filtered from the Science Citation Index Expanded (SCI-Expanded). Analysis software tools such as CiteSpace and VOSviewer were employed for multifaceted analyses encompassing economic indices, geographical research dissemination, journal co-citation metrics, authorial contributions, citation evaluations, and burst analytics. In the dimension of clinical trials, we interrogated databases including ClinicalTrials.gov (https://www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (https://trialsearch.who.int). A total of 239 clinical trials were initially sourced, among which, 175 were from ClinicalTrials.gov and 64 from ICTRP. After repetitive and correlation-based screening, 119 trials specifically addressing ADC therapeutic strategies in breast cancer were included. Analytical algorithms were executed using Microsoft-based software to evaluate treatment paradigms, emergent research themes, and progress trajectories. Results Our investigations signify a burgeoning research milieu in ADCs, with consistent advancements in scientific achievements. The analysis revealed that variables such as economic stratification of nations, healthcare investment paradigms, and disease incidence rates serve as significant determinants in shaping research output. Geographically, the United States emerged as the predominant contributor to the research corpus (36.56%), closely followed by China (21.33%). The underpinning of research accomplishments was found to be significantly bolstered by advancements in molecular biology, immunology, and genetic research. Moreover, the advent of nuclear magnetic resonance diagnostic modalities has contributed saliently to the diagnostic and therapeutic management of breast cancer. Conclusion Our study encapsulates a holistic view of the ADC research landscape through rigorous bibliometric and clinical trial evaluations. At present, the ADC arena has witnessed the successful development and FDA approval of 14 distinct agents, substantially improving the clinical outcomes for a broad spectrum of oncological patients. Future research imperatives may include the exploration of ADCs targeting mutated oncoproteins, dual-specificity ADCs, combination payload strategies, peptide-drug conjugates (PDCs), and non-internalizing ADC modalities. With sustained academic and clinical focus, the ADC domain is poised for transformative advancements in targeted therapeutics across a variety of malignancies.

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Targeting HER3 for cancer treatment: a new horizon for an old target

Cited by 35 publications

References 48 publications

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors

HER3 overexpression: a predictive marker for poor prognosis in advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors

Antibody-Drug Conjugates for Breast Cancer: A Bibliometric Study and Clinical Trial Analysis

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