HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer

Abstract

Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC < 80 nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

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

“…The authors postulated that the irreversible, covalent nature of neratinib binding, as opposed to the reversible, non-covalent lapatinib binding, explains this difference. A later study by Canonici et al provided similar results and is covered in more detail in Section 4.4 [53].…”

“…Neratinib was compared with lapatinib and with afatinib, another irreversible pan-HER TKI, in a panel of 11 HER2+ breast cancer cell lines [53]. Neratinib was more potent than lapatinib in all 11 cell lines in this study and was more potent than afatinib in nine.…”

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

“…Previous studies have highlighted the higher potency of neratinib compared to lapatinib. 30 Based on IC 50 values, neratinib displayed the most potent anti-proliferative effect of the three HER2-targeted TKIs, displaying on average 7 and 14 times higher potency than lapatinib and tucatinib, respectively. Neratinib showed the most cancer-type agnostic activity, with 19 of the 25 cancer tissue types included in the study having at least one cell line achieve a sub-micromolar IC 50 value.…”

Tyrosine Kinase Inhibitor Imatinib Mesylate Alters DMBA-Induced Early Onco/Suppressor Gene Expression with Tissue-Specificity in Mice

“…Protein tyrosine kinase inhibitors are small molecules that are able to diffuse through the cell membrane targeting cytoplasmic kinases or the intracellular domain of receptor tyrosine kinases. TKIs are currently booming and are widely used in cancer cure either in the form of monotherapy or in combination with other chemotherapeutic agents [58].…”