Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer

Abstract

Breast cancer (BC) is caused by epigenetic modifications and genetic heterogeneity and exhibits various histological feature. HER2+ (Human epidermal growth factor receptor 2) is a more aggressive type of breast cancer, diagnosis and prognosis are difficult for HER2+ BC. Anti-HER2+ inhibitors have been effectively used for patient treatment. High mortality rate is reported in HER2+ BC, due to availability of limited therapeutic options. Despite advances in systemic medications to treat metastatic breast cancer (MBC), HER2-positive MBC is still challenging for patients and treating clinicians. The clinical characteristics of the disease have changed after treatment with HER2-targeted therapy. Various types of Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with HER2+ BC including afatinib, lapatinib, neratinib, tucatinib, and pyrotinib, have been developed as HER2-targeted therapies. The antibody-drug conjugates adotrastuzumab, emtansine, famtrastuzumab, and deruxtecan, as well as the anti-HER2 monoclonal antibody pertuzumab are used in both early-stage and metastatic situations, either alone or in conjunction with chemotherapy and other HER2-targeting therapies. The emergence of drug resistance in anti-HER2 therapies has been observed. To overcome drug resistance and limited efficacy in current treatment options, nano formulations can be used in patients with HER2+ BC treatment. Anti-HER2 ligands can be used in various nano formulations to target HER2 receptors. Here we will discuss, targeted TKIs in patients with HER2+ BC, clinical studies of HER2+ targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2+ MBC (metastatic breast cancer) and anti-HER2 ligand in various nano formulations to target HER2 receptors.

Epidermal growth factor receptor inhibition potentiates chemotherapeutics‐mediated sensitization of metastatic breast cancer stem cells

“…The efficiency of EGFR‐TKIs used in targeted cancer treatment regimens is often restricted to the emergence of acquired resistance targeting drug‐resistant mutants of EGFR 10–12 . Currently, the available EGFR‐TKIs generally target the ATP binding site of the EGFR kinase domain, necessitating the need for therapeutic agents with alternative mechanisms of action for overcoming resistance to EGFR mutants 41 . Caporuscio et al have shown the design and development of small affinity molecules by a cost‐effective, high throughput docking method for identifying allosteric interaction sites of EGFR 42 .…”

“… 10 , 11 , 12 Currently, the available EGFR‐TKIs generally target the ATP binding site of the EGFR kinase domain, necessitating the need for therapeutic agents with alternative mechanisms of action for overcoming resistance to EGFR mutants. 41 Caporuscio et al have shown the design and development of small affinity molecules by a cost‐effective, high throughput docking method for identifying allosteric interaction sites of EGFR. 42 To date, several clinical trials have been performed to assess the efficiency of TKIs in breast cancer and the results are ineffective owing to the monotherapy treatment regime.…”

In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells

“…Since trastuzumab is representative of the standard treatment of HER-2 positive breast tumors, we studied its effect in combination with the PPRHs against the ERBB2 gene. In this sense, the rationale for a combination of trastuzumab with either chemotherapy such as capecitabine or paclitaxel, or with tyrosine kinase inhibitors such as lapatinib, or more recently with a dual inhibitor of both mTOR and PI3K, has proved to be a more potent approach for HER-2-positive breast cancer treatment than trastuzumab alone [ 24 ]. Nowadays, the combined therapy of trastuzumab, pertuzumab, and taxane is the standard for treating metastatic breast cancer [ 25 ].…”

Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS)

“…Due to the reliability of HER2 as a target antigen, the types of HER2 inhibitors are diversifying. Currently, there are three main types of HER2 inhibitors used in clinical practice: small-molecule drugs (lapatinib, neratinib, tucatinib, and pyrotinib), monoclonal antibodies (trastuzumab, pertuzumab), and antibody-conjugated drugs (ADCs): TDM-1, T-DXd, et al ( Schlam and Swain, 2021 ; Singh et al, 2022 ; Banys-Paluchowski et al, 2023 ). For example, many guidelines recommend the combination of trastuzumab, pertuzumab, and taxane as the standard first-line treatment for patients with advanced HER2+ BC ( Swain et al, 2020 ).…”