PURPOSE: Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment. RESULTS: Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control. CONCLUSION: The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
PURPOSE:Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment. RESULTS: Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control. CONCLUSION: The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Authors: David A Reardon; James J Vredenburgh; Annick Desjardins; Katherine B Peters; Sith Sathornsumetee; Stevie Threatt; John H Sampson; James E Herndon; April Coan; Frances McSherry; Jeremy N Rich; Roger E McLendon; Steven Zhang; Henry S Friedman Journal: J Neurooncol Date: 2012-03-10 Impact factor: 4.130
Authors: Marwa Ali A Fathi; Amer Ali Abd El-Hafeez; Dalia Abdelhamid; Samar H Abbas; Monica M Montano; Mohamed Abdel-Aziz Journal: Bioorg Chem Date: 2018-11-22 Impact factor: 5.275
Authors: John H Strickler; Shannon McCall; Andrew B Nixon; John C Brady; Herbert Pang; Christel Rushing; Allen Cohn; Alexander Starodub; Christy Arrowood; Sherri Haley; Kellen L Meadows; Michael A Morse; Hope E Uronis; Gerard C Blobe; S David Hsu; S Yousuf Zafar; Herbert I Hurwitz Journal: Invest New Drugs Date: 2013-11-01 Impact factor: 3.850
Authors: Athanassios Argiris; Trevor M Feinstein; Lin Wang; Tianbing Yang; Shruti Agrawal; Leonard J Appleman; Ronald G Stoller; Jennifer R Grandis; Ann Marie Egloff Journal: Invest New Drugs Date: 2011-09-01 Impact factor: 3.850
Authors: Andrew M Brunner; Daniel B Costa; Rebecca S Heist; Elizabeth Garcia; Neal I Lindeman; Lynette M Sholl; Geoffrey R Oxnard; Bruce E Johnson; Peter S Hammerman Journal: J Thorac Oncol Date: 2013-11 Impact factor: 15.609
Authors: Ellen M Beauchamp; Brittany A Woods; Austin M Dulak; Li Tan; Chunxiao Xu; Nathanael S Gray; Adam J Bass; Kwok-kin Wong; Matthew Meyerson; Peter S Hammerman Journal: Mol Cancer Ther Date: 2013-12-02 Impact factor: 6.261