The Role of Tumor-Associated Antigen HER2/neu in Tumor Development and the Different Approaches for Using It in Treatment: Many Choices and Future Directions

Abstract

The treatment of HER2-positive cancers has changed significantly over the past ten years thanks to a significant number of promising new approaches that have been added to our arsenal in the fight against cancer, including monoclonal antibodies, inhibitors of tyrosine kinase, antibody–drug conjugates, vaccination, and particularly, adoptive-T-cell therapy after its great success in hematological malignancies. Equally important is the new methodology for determining patients eligible for targeted HER2 therapy, which has doubled the number of patients who can benefit from these treatments. However, despite the initial enthusiasm, there are still several problems in this field represented by drug resistance and tumor recurrence that require the further development of new more efficient drugs. In this review, we discuss various approaches for targeting the HER2 molecule in cancer treatment, highlighting their benefits and drawbacks, along with the different mechanisms responsible for resistance to HER2-targeted therapies and how to overcome them.

Target-Driven Tissue-Agnostic Drug Approvals; a New Path of Drug Development

“…Activated HER2 can interact with MAPK and PI3KT/AKT pathways, promoting tumor cell growth. HER2 positivity have been reported in bladder cancer (16%), esophageal cancer (14.9%), breast cancer (18.3%), gallbladder cancer (11.11%), cholangiocarcinoma (8.5%), gastric adenocarcinoma (17.3%), ovarian cancer of epithelial origin (8.16%), and various head and neck cancers (4-19%) [40]. The HER2 expression is often measured by the immunohistochemistry (IHC) score.…”

“…The ORR was 33.3% (95% CI 29.2-37.6), including 10.3% CR and a 23% PR. The response rate among 124 patients with metastatic colorectal cancer was 34% (95% CI [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] with DOR ranging between 4.4 and 58.5 months. There were also 380 patients with non-colorectal cancer that had an ORR of 33% as well as a duration of response ranging between 1.9 and 63.9 months.…”

An Insight on Functioning Pancreatic Neuroendocrine Neoplasms

“…Although large deletions or amplifications are relatively rare, gastrinoma is characterized by amplification of the HER-2/neu protooncogene or chromosome 9q, deletion of the p16/MTS1 tumor suppressor gene or deletion of chromosome 3p [119]. Amplification of HER2 receptor triggers signaling cascades leading to activation of key pathways involved in tumor development, such as Ras/MEK/ERK, JAK/STAT, and PI3K/AKT [120]. The protein p16 is encoded by the cyclin-dependent kinase inhibitor 2A (CDKN2A) or multiple tumor suppressor 1 (MTS1) gene.…”

Prophylactic Vaccination and Intratumoral Boost with HER2-Expressing Oncolytic Herpes Simplex Virus Induces Robust and Persistent Immune Response against HER2-Positive Tumor Cells

“…Overexpression of HER2 is observed in various types of cancer. Additionally, it is important to note that HER2 overexpression is linked to a more aggressive form of the disease, a higher incidence of recurrence, and a shorter overall survival time [ 14 ].…”