Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

• Todd A. Carter

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Lisa M. Wodicka

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Neil P. Shah

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Anne Marie Velasco

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Miles A. Fabian

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Daniel K. Treiber

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Zdravko V. Milanov

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Corey E. Atteridge

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• William H. Biggs

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Philip T. Edeen

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Mark Floyd

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Julia M. Ford

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Robert M. Grotzfeld

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Sanna Herrgard

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Darren E. Insko

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Shamal A. Mehta

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Hitesh K. Patel

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• William Pao

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Charles L. Sawyers

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Harold Varmus

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• Patrick P. Zarrinkar

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

• David J. Lockhart

  Ambit, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121; Division of Hematology and Oncology, Department of Medicine, and Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021

抄録

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved “gatekeeper” threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 102 (31), 11011-11016, 2005-07-26

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1363951793253252096
• NII論文ID: 80017805360
• DOI: 10.1073/pnas.0504952102
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0504952102
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