2. Academic Validation
  3. Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models

Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models

  • Cancer Lett. 2019 Apr 10;447:105-114. doi: 10.1016/j.canlet.2019.01.024.
Tingting Lu 1,  Cheng Chen 2,  Aoli Wang 3,  Zongru Jiang 2,  Ziping Qi 3,  Zhenquan Hu 3,  Chen Hu 3,  Feiyang Liu 3,  Wenliang Wang 2,  Hong Wu 3,  Beilei Wang 2,  Li Wang 2,  Shuang Qi 3,  Jiaxin Wu 3,  Wenchao Wang 3,  Jun Tang 4,  Hezhong Yan 4,  Mingfeng Bai 5,  Qingsong Liu 6,  Jing Liu 7
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, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR 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, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR 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, 230031, PR China.
  • 4 The People's Liberation Army Joint Service Support Force No. 901 Hospital, Hefei, Anhui, 230031, PR China.
  • 5 Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15219, United States.
  • 6 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, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address: [email protected].
  • 7 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, 230031, PR China. Electronic address: [email protected].
PMID: 30684595 DOI: 10.1016/j.canlet.2019.01.024
Abstract

Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.

Keywords

Activation loop mutants; Drug resistance; cKIT T670I mutant.

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