Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and Lapatinib

Abstract

The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC 50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G 0 -G 1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978-87. Ó2012 AACR.

Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth

“…1A). These cell lines have all been well characterized as HER2-dependent for their proliferation (14,21,22). In contrast, other breast cancer cell lines with no HER2 amplification had little or no sensitivity to ibrutinib (Fig.…”

“…Several recently developed TKIs are capable of forming covalent bonds with the conserved cysteine in the ATP-binding pocket (10)(11)(12)(13)(14). Although TKIs are highly effective in targeting ERBB kinases, ibrutinib could have additional desirable effects in solid tumor settings based on its concurrent activity against TEC family kinases.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Dacomitinib (PF-00299804) is a second-generation irreversible pan-HER TKI related to canertinib, but with better pharmacokinetic and bioavailability properties [171,172]. Although HER2/neu is subject to inhibition by this agent, the overwhelming bulk of its development has focused on its inhibition of EGFR (HER1) [171][172][173]. In Phase I studies, dacomitinib did not appear to have the same variability in maximumtolerated dose, established at 60 mg daily, by schedule and route as in the first-generation pan-HER inhibitor canertinib [174][175][176].…”

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

“…It has been associated with antitumor effects in breast cancer cell lines that were resistant to trastuzumab and lapatinib [65]. It was also found to offer improved progression-free survival compared to erlotinib in advanced non-small cell lung cancer (NSCLC) [66].…”