Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

Abstract

An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

“…List of FDA-approved small molecule protein kinase inhibitors (updated by 18 August 2019). These inhibitors are sorted by their main targeted pathways and from signal initiation at cytoplasmic membrane of the cell to its propagation to the nucleus [13,[15][16][17][18][19].…”

Sodium-Dependent Glucose Transporter 1 (SGLT1) Stabled by HER2 Promotes Breast Cancer Cell Proliferation by Activation of the PI3K/Akt/mTOR Signaling Pathway in HER2+ Breast Cancer

“…Association of SGLT1 expression levels with (b) DFS and (d) OS in HER2+ breast cancer patients. 9 Disease Markers ECAR, which indirectly reflects glycolysis, is also affected by HER2 or SGLT1 inhibition. The ECAR pattern reflected the SGLT1 expression pattern.…”

“…Although significant improvements in DFS and OS have been achieved by comprehensive adjuvant therapy [6], breast cancer patients diagnosed at advanced stages still have poor prognosis [7]. The HER2+ subtype accounts for 15-20% of breast cancer cases and is prone to recurrence and metastasis [8,9]. Several anti-HER2 monoclonal antibodies and receptor tyrosine kinase inhibitors have been approved by the FDA [10].…”

Long Non-Coding RNA: Dual Effects on Breast Cancer Metastasis and Clinical Applications

“…It is critical to select the chemotherapy regimens wisely, because different types of BC will respond to different regiments and specific drugs. For example, ribociclib plus fulvestrant (hormone receptor-positive/HER-2+) [152]; trastuzumab, neratinib and lapatinib (HER-2+) [153,154]; or ipatasertib plus paclitaxel (TNBC) [155]. Working on distinct molecular mechanisms, these chemotherapies act synergistically and eliminate most tumor cells during the initial treatment phase.…”