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Clinical Trial
. 2021 Mar 1;27(5):1463-1475.
doi: 10.1158/1078-0432.CCR-20-3555. Epub 2020 Dec 22.

Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes

Adriana Estrada-Bernal  1 , Anh T Le  1 , Andrea E Doak  1 , Vijaya G Tirunagaru  2 , Shevan Silva  3 , Matthew R Bull  3   4 , Jeff B Smaill  3   4 , Adam V Patterson  3   4 , Chul Kim  5 , Stephen V Liu  5 , Robert C Doebele  6
Affiliations
Clinical Trial

Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes

Adriana Estrada-Bernal (VSports app下载) et al. Clin Cancer Res. .

Abstract

Purpose: Approved therapies for EGFR exon 20, ERBB2 mutations, and NRG1 fusions are currently lacking for non-small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR VSports手机版. .

Experimental design: Novel and existing patient-derived cell lines and xenografts harboring EGFR exon 20 insertion mutations, ERBB2 mutations and amplification, and NRG1 fusions were tested in vitro and in vivo with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling V体育安卓版. .

Results: Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models in vitro by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. In vivo, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models V体育ios版. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an ERBB2 exon 20 p. A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib. .

Conclusions: Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients. VSports最新版本.

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Conflict of interest statement

COI: AEB, AED, SS, and MRB, these authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Tarloxotinib-E inhibits ErbB family member phosphorylation and downstream signaling in EGFR-, HER2- or NRG1-driven cell lines.
Cells were treated with the indicated doses (nmo/L) of afatinib, gefitinib, osimertinib or tarloxotinib-E (active drug) for 2 hours, lysed and analyzed by immunoblot for the indicated proteins. A) CUTO14 cell line (EGFR exon 20 insertion mutation). B) H1781 (HER2 exon 20 insertion mutation). C) MDA-MB-175vII (NRG1 fusion cell line). Representative images of blots are shown. Experiments were performed in triplicate.
Figure 2.
Figure 2.. Tarloxotinib-E inhibits proliferation of cell lines harboring EGFR, HER2, or NRG1 oncogenes.
Dose response curves of cell proliferation of A) CUTO14, CUTO17, and CUTO18 (EGFR ex20ins); B) H1781 (HER2 ex20ins), H2170 and Calu-3 (HER2 amp) and C) MDA-MB-175VIII (breast cancer, DOC4-NRG1 fusion) and H661 (HER4 overexpression). Cells were treated with tarloxotinib (prodrug) or tarloxotinib-E (active drug) for 72 hours and analyzed by MTS assay. Experiments were done in triplicate; mean ± SEM is plotted.
Figure 3.
Figure 3.. Tarloxotinib inhibits tumor growth of EGFR exon 20 mutant, HER2 gene altered, or NRG1 fusion models in vivo.
The percent change from baseline tumor volume was graphed for nude mice inoculated subcutaneously with the indicated cell lines; A) CUTO14 or CUTO17 (EGFR ex20ins); B) H1781 (HER2 ex20ins) or Calu-3 cells (HER2 amp). C) PDX model (OV-10–0050) with a CLU-NRG1 fusion. Mice were treated with vehicle, tarloxotinib (26 mg/kg or 48 mg/kg, once weekly, IP) and afatinib (6 mg/kg, daily, PO) for 4 weeks. Mean ± SEM is plotted. Statistical analysis was made using 2-way-ANOVA, *p<0.005, **p<0.02.
Figure 4.
Figure 4.. Pharmacological profile of tarloxotinib and tarloxotinib-E in mice bearing the PDX model (OV-10–0050).
After single dose of tarloxotinib, tumor, skin and blood were collected at 2, 24 and 168 hours. Tarloxotinib and tarloxotinib-E concentration was measured for each time point. Mean ± SEM is plotted.
Figure 5.
Figure 5.. Tumor hypoxia levels in xenograft models.
Mice were dose with pimonidazole HCl (60 mg/kg, IP) one hour before tumor collection. Tissue was fixed, paraffin embedded and process for immunofluorescence. The primary antibody Mab1 binds to protein adducts of pimonidazole in hypoxic cells (green). Cytokeratin staining was used to evaluate tumor content (red). All images were capture at 20× using an Olympus IX83 microscope. Scale bars are 1mm or 500μm as indicated in the figures. A) Images representing vehicle and treated CUTO14 xenografts. Red square in green channel indicates the higher magnification area. B) Total area and cytokeratin positive area in vehicle and treated CUTO14 xenografts. * p< 0.005. C) Percent of total area positive hypoxia staining in CUTO14 and H1781 xenografts. Mean ± SEM is plotted.
Figure 6.
Figure 6.. Radiologic response to tarloxotinib.
Baseline imaging obtained prior to dosing with tarloxotinib (150 mg/m2 IV weekly) showed bulky right hilar mass, right pleural effusion, and bilateral adrenal gland lesions (red arrows) (A). A marked tumor response with decreased size of right hilar mass, right pleural effusion, and lesions in the adrenal glands was observed at week 4 (B) and week 12 (C).
See this image and copyright information in PMC

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