Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified AE EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. Mol Cancer Ther; 14(7); 1548-58. Ó2015 AACR.

Section: Introductionmentioning

confidence: 99%

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Zahonero

Aguilera

Ramírez-Castillejo

et al. 2015

“…1) is a second-generation irreversible pan-HER receptor tyrosine kinase inhibitor (selectively inhibiting EGFR, HER2, and HER4) under clinical development (16,17). Dacomitinib showed marked activity in several xenograft models with variable levels of HER family receptors, including lung tumors resistant to EGFR small molecule tyrosine kinase inhibitors (16,18). The primary aim of this study was to describe the in vitro activity of dacomitinib in a panel of 47 human breast cancer and immortalized breast cell lines, to identify potential biomarkers of response and/or resistance to guide clinical development.…”

Section: Introductionmentioning

confidence: 99%

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

Kalous

Conklin

Desai

et al. 2012

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.

“…PF00299804 has been shown to induce objective responses during phase I and II trials in patients with EGFR TKI-refractory non-small cell lung cancer (NSCLC; refs. [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Antitumor Effects and Mechanisms of PF00299804, a Pan-HER Inhibitor, Alone or in Combination with Chemotherapy or Targeted Agents in Gastric Cancer

Nam

Ching

Kan

et al. 2012

Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models.