HER3 Alterations in Cancer and Potential Clinical Implications

Kilroy, Mary Kate; Park, SoYoung; Feroz, Wasim; Patel, Hima; Mishra, Rosalin; Alanazi, Samar; Garrett, Joan T.

doi:10.3390/cancers14246174

Cited by 10 publications

(9 citation statements)

References 149 publications

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“…The HER3/HER2 and HER3/EGFR axes can be triggered in TNBC by different factors, such as upregulation of neuregulin or EGFR (21,22,86). It is associated with a poor prognosis and therapeutic resistance (21,87,88). However, the blockage of HER3 did not show any clinical benefit.…”

Section: Other Adcs Under Investigationmentioning

confidence: 98%

“…However, EGFR-targeted therapy did not show any benefit in TNBC (20). One of the reasons for this resistance is the activation of human epidermal growth factor receptor 3 (HER3), which is one of the four members of the HER family, along with HER2, EGFR (HER1), and HER4, and the main dimerization partner of EGFR (21). Upregulation of HER3 or its ligand, neuregulin, could be demonstrated in cell lines of TNBC of the BL type but not in the claudin-low subtype (22).…”

Section: Molecular Subtypes Of Triplenegative Breast Carcinomasmentioning

confidence: 99%

“…Upregulation of HER3, an important partner of EGFR, HER2, and HER4, is described in various cancers. Although the significance of HER3 is highlighted in HR-positive and HER2positive breast cancers, TNBCs are also influenced by some of its functions (21). The HER3/HER2 and HER3/EGFR axes can be triggered in TNBC by different factors, such as upregulation of neuregulin or EGFR (21,22,86).…”

Section: Other Adcs Under Investigationmentioning

confidence: 99%

“…Although the significance of HER3 is highlighted in HR-positive and HER2positive breast cancers, TNBCs are also influenced by some of its functions (21). The HER3/HER2 and HER3/EGFR axes can be triggered in TNBC by different factors, such as upregulation of neuregulin or EGFR (21,22,86). It is associated with a poor prognosis and therapeutic resistance (21,87,88).…”

Section: Other Adcs Under Investigationmentioning

confidence: 99%

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Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

Carvalho

2023

Front. Oncol.

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Triple-negative breast cancers (TNBCs) are more likely to occur in younger patients and have a poor prognosis. They are highly heterogeneous tumors consisting of different molecular subtypes. The only common characteristic among them is the absence of targets for endocrine therapy and human epidermal growth factor receptor 2 (HER2) blockade. In the past two decades, there has been an increased understanding of these tumors from a molecular perspective, leading to their stratification according to new therapeutic strategies. TNBC has ushered breast carcinomas into the era of immunotherapy. The higher frequency of germline BRCA mutations in these tumors enables targeting this repair defect by drugs like PARP inhibitors, resulting in synthetic lethality in neoplastic cells. Additionally, we have the identification of new molecules to which this generation of smart drugs, such as antibody-drug conjugates (ADCs), are directed. In this review, we will discuss the trajectory of this knowledge in a systematic manner, presenting the molecular bases, therapeutic possibilities, and biomarkers.

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Section: Other Adcs Under Investigationmentioning

confidence: 98%

Section: Molecular Subtypes Of Triplenegative Breast Carcinomasmentioning

confidence: 99%

Section: Other Adcs Under Investigationmentioning

confidence: 99%

Section: Other Adcs Under Investigationmentioning

confidence: 99%

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Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

Carvalho

2023

Front. Oncol.

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“…HER3 is widely expressed in mCRC, and elevated HER3 expression was shown to be an independent prognostic factor that was associated with poor outcomes [ 37 ]. HER3 displays intrinsically low kinase activity and must dimerize with either another EGFR-family member, including HER2 and EGFR, or a non-EGFR receptor tyrosine kinase (RTKs), including fibroblast growth factor receptor (FGFR), MET, or Axl to stimulate cell survival and proliferation signaling [ 38 ]. HER3 was also shown to be upregulated in CRC cells in response to factors secreted from liver endothelial cells (ECs), and blocking HER3 using a humanized anti-HER3 mAb seribantumab inhibited EC-induced CRC survival [ 39 ].…”

Section: Targeting Egfr In Mcrcmentioning

confidence: 99%

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

Gmeiner

2024

Cancers

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Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.

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

Mishra,

Kilroy,

Feroz

et al. 2024

Molecular Carcinogenesis

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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.

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HER3 Alterations in Cancer and Potential Clinical Implications

Cited by 10 publications

References 149 publications

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

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

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