Original Article

Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 6, pp 1065-1074

Open Access This content is freely available online to anyone, anywhere at any time.

Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL™), a multi-targeted kinase inhibitor

  • Feng (Roger) LuoAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Yu Chen BarrettAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company Email author 
  • , Zheng YangAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Amy CamusoAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Kelly McGlincheyAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Mei-Li WenAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Richard SmyklaAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Krista FagerAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
  • , Robert WildAffiliated withOSI Pharmaceuticals Inc., In Vivo Pharmacology
    • , Holly PalmeAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
    • , Susan GalbraithAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
    • , Anne Blackwood-ChirchirAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company
    • , Francis Y. LeeAffiliated withPharmaceutical Research Institute, Clinical Discovery, Bristol-Myers Squibb Company

Abstract

Purpose

Dasatinib (BMS-354825) is a potent, oral multi-targeted kinase inhibitor. It is an effective therapy for patients with imatinib-resistant or -intolerant Ph+ leukemias,. It has demonstrated promising preclinical anti-tumor activity, and is under clinical evaluation in solid tumors. To support the clinical development of dasatinib, we identified a pharmacodynamic biomarker to assess in vivo SRC kinase inhibition, with subsequent evaluation in cancer patients.

Methods

The biomarker, phosphorylated SRC (phospho-SRC), was first identified in human prostate PC-3 tumor cells and peripheral blood mononuclear cells (PBMCs) in vitro. It was further assessed in nude mice bearing PC-3 xenografts. Phospho-SRC[pY418] in tumors and PBMC were measured by western blot analysis, and were quantified by ELISA assays. Dasatinib plasma concentrations were determined using LC/MS/MS.

Results

In PC-3 cells, dasatinib showed dose-dependent anti-proliferative effect, which correlated with the inhibition of phospho-SRC[pY418] and of SRC kinase activity. With a single oral dose of 50 or 15 mg/kg, tumoral phospho-SRC[pY418] was maximally inhibited at 3 h, partially reversed between 7 and 17 h, and completely recovered after 24 h post dose. At 5 mg/kg, tumoral phospho-SRC[pY418] inhibition was less pronounced and recovered more rapidly to baseline level within 24h. Dasatinib (1 mg/kg) resulted in little inhibition. In PBMCs, a similar time course and extent of phospho-SRC[pY418] inhibition was observed. Inhibition of phospho-SRC[pY418] in vivo appeared to correlate with the preclinical in vivo efficacy and PK profiles of dasatinib in mice.

Conclusions

Phospho-SRC[pY418] may potentially be used as a biomarker to enable assessment of target inhibition in clinical studies exploring dasatinib antitumor activity.

Keywords

Dasatinib Pharmacodynamics Biomarker SRC Pharmacokinetics