2. Academic Validation
  3. Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors

Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors

  • Ther Adv Med Oncol. 2019 May 17;11:1758835919849757. doi: 10.1177/1758835919849757.
Feiyang Liu 1,  Fengming Zou 1,  Cheng Chen 2,  Kailin Yu 2,  Xiaochuan Liu 3,  Shuang Qi 1,  Jiaxin Wu 2,  Chen Hu 2,  Zhenquan Hu 1,  Juan Liu 2,  Xuesong Liu 2,  Li Wang 2,  Juan Ge 2,  Wenchao Wang 1,  Tao Ren 4,  Mingfeng Bai 5,  Yujiao Cai 6,  Xudong Xiao 7,  Feng Qian 8,  Jun Tang 9,  Qingsong Liu 10,  Jing Liu 11
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, P. R. China.
  • 2 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China University of Science and Technology of China, Hefei, Anhui, P. R. China.
  • 3 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
  • 4 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, P. R. China Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
  • 5 Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 6 Department of General Surgery, Second Hospital Affiliated to Army Medical University, Chongqing, P. R. China.
  • 7 Department of Anesthesiology, Second Hospital Affiliated to Army Medical University, Chongqing, P. R. China.
  • 8 Department of General Surgery, Southwest Hospital Affiliated to Army Medical University, Chongqing, P. R. China.
  • 9 Department of Gastroenterology, The People's Liberation Army Joint Logistics Support Force No. 901 Hospital, Hefei, Anhui 230031, P. R. China.
  • 10 High Magnetic Field Laboratory, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China University of Science and Technology of China, Hefei, Anhui 230036, P. R. China Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, P. R. China.
  • 11 High Magnetic Field Laboratory, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
PMID: 31205508 DOI: 10.1177/1758835919849757
Abstract

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells.

Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib.

Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models.

Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

Keywords

GISTs; axitinib; cKIT; cKIT T670I; drug resistance.

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